DM1 is one of the most variable hereditary human disorders in terms of its range of clinical manifestations, severity of illness, and age at onset.20,21
Despite the diversity and variable severity of its symptoms, our study demonstrates the feasibility of determining which aspects of the disease are most significant to affected individuals. This study fills an important gap in the present literature. It supplies information that is needed worldwide by groups who are planning clinical trials. It directly addresses a key question that is frequently asked by researchers, clinicians, industry, and regulatory agencies: what features of the illness are most important to affected individuals? This work also provides the base data necessary to develop future disease-specific, patient-relevant outcome measures for this population.
Patient Reported Impact of Symptoms in Myotonic Dystrophy Type 1 (PRISM-1) builds on previous studies of disease burden in DM1 that were limited by small sample sizes, restricted geographical range, or marginal patient input.22–24
This study shows that there are specific manifestations and symptoms that have both a common and significant effect on lives of patients with DM1. These patient-identified symptoms represent the key physical, mental, and social features of DM1 disease burden. In addition, our findings indicate the rate at which the prevalence and importance of symptoms change by patient age, duration of symptoms, and number of CTG repeats.
In this study we focused on the patient's point of view instead of prior medical reviews or opinion.24
Researchers have previously shown that noncarrier perceptions of the disability and impairment in DM1 correlate poorly with actual patient views.25
We determined the prevalence and severity of each DM1 symptom and theme using direct patient input. This is in response to the FDA and the patient-oriented research community who state that research of this type should ideally be patient-centric and antipaternalistic.13,26
The emphasis of PRISM-1 on the patient's perspective strongly enhances the content validity of the data; however, we recognize that this approach may deemphasize certain manifestations that are below patients' conscious awareness, such as asymptomatic respiratory or cardiac disease. Ultimately, correlation studies may determine the relative sensitivity of patient-reported data to traditional functional assessments in detecting subtle DM1 disease progression.
This patient-centered research demonstrates that the most prevalent (or well described) manifestations in a population are not always the manifestations that have the greatest effect on patients' lives. The medical literature does not generally report fatigue as the primary symptom of DM1; however, participants reported this symptom as having the greatest overall effect. It is likely that fatigue also has indirect effects on other key issues in DM1, such as employment status and interpersonal relations. It should be noted that “fatigue” may represent many additional issues in DM1 including tired muscles, decreased energy, prolonged recovery after exercise, daytime sleepiness, depression, impaired sexual function, problems with concentration, and decreased motivation. Interestingly, none of these issues in isolation had a population impact score as high as that for Fatigue during this study.
In some cases, there was dissociation between the prevalence of a theme and its relative importance. Whereas Problems with hands or arms had the highest theme prevalence, it did not have the highest impact score. Limitations with mobility or walking only had the sixth highest theme prevalence; however, of the patients who reported this issue, it had the second highest effect on their lives. Similarly, difficulty having children had the highest impact score of any item; however, only a relatively small portion (34.2%) of participants, consisting mainly of women, stated that they experienced this issue. Although this question was initially intended to address fertility issues, it is possible that participants instead viewed it in other terms.
The increase in composite prevalence and impact scores between the 21- to 30-year-old age group and the 31- to 40-year-old age group raises the possibility that the effect of major disease manifestations in DM1 does not progress linearly with age and that there is a period of accelerated disease progression in DM1. If confirmed in a longitudinal study, this information may provide a valuable counseling tool to be used with patients in a clinical setting and identify a critical therapeutic window in DM1.
The average composite impact score over all themes increased with CTG repeat length. Although this finding supports the often debated theory that DM1 disease severity is related to a patient's CTG repeat length, there are probably many additional genetic and environmental factors that contribute to DM1 disease severity.27–29
A notable observation was that the effect of the disease (as measured by the average composite impact score over all themes) did not universally increase with age despite increases in the prevalence of themes. This phenomenon may be due to additional unmeasured factors (e.g., experience, coping, improved social networks, or improved financial status) that help lessen the burden of disease as age increases. Another possible explanation is a survivor effect (a type of sampling bias in which an older group of participants may be healthier than the general population of people with the disease) or other sampling bias. It is possible that sicker participants with DM1 who were older were less likely to participate in the survey (or may even have failed to survive past the age of 60), leaving a healthier subset of older participants with DM1. Another possibility is that this group represents a late-onset and relatively asymptomatic subgroup of patients with DM1 who came to diagnosis through family studies and not necessarily through progression of their own disease.
The effect of DM1 manifestations is not markedly different between women and men. Although women with DM1 did have a higher prevalence of Gastrointestinal issues and men with DM1 more frequently reported Communication difficulties, these differences may be present in the general population and are not necessarily specific to DM1.30
The limitations of this study are similar to those of any cross-sectional study evaluating a rare disease that progresses over time. Although the registry used represents a wide range of ages and geographic locations, this sample does not perfectly represent the DM1 population. In addition, not every eligible patient from the registry participated in this research. To this end, there is the potential for sampling bias that could affect the generalizability of our results. Our study sample probably overrepresents patients with DM1 who seek medical attention, are interested in medical research, are less affected, and have the means, cognitive abilities, and physical function necessary to take part in research. Because participants did not report medication use, it is also possible that our sample underreported symptoms related to treated manifestations of DM1 (such as participants receiving antimyotonia therapy or stimulants for excessive daytime sleepiness).
PRISM-1 demonstrates that through rigorous qualitative and quantitative methods it is possible to obtain a patient-centered description of the most common and relevant aspects of disease burden in DM1, including the discovery of manifestations that were not as well recognized before. Systematic efforts like this may be fruitful in many other diseases. Ultimately, the information gained from this study can be used to 1) better understand the multiple systemic involvement of DM1, 2) demonstrate how DM1 disease varies with time and accordingly to CTG repeat length, and 3) better equip researchers and clinicians with the ability to identify, study, and focus on the manifestations that are most important to those affected by DM1.