Successes and limitations
A diverse group of myotonic dystrophy patients have registered, providing a cross-sectional snapshot of the myotonic dystrophy population in the UK and the contribution from healthcare professionals (clinicians, nurse specialists and physiotherapists) across the country has helped establish a virtual network of medical professionals with an interest in myotonic dystrophy and research into the condition [
23]. The registry has successfully supported recruitment into several academic research studies, including the international trial OPTIMISTIC [
24] (NCT02118779), the national deep-phenotyping study Pheno-DM1 (NCT02831504), and a pilot longitudinal study at the University of Nottingham. In each case local clinic-based recruitment was supplemented with nationwide registry recruitment, the latter accounting for 30–50% of study participants. In addition, the registry is supporting recruitment and feasibility for the first commercial clinical trial in the UK (NCT02858908). It has also been utilised as a research tool to help the National Institutes of Health (USA) with ongoing research into myotonic dystrophy and cancer, as well being part of an international effort to collect additional information on common adverse events.
There are limitations to a patient initiated registry and the design of this registry does include an element of self-selection, therefore we cannot assume this cohort is fully representative of the entire DM1 population in the UK. The nature of the registry means that inclusion is biased towards those that are able, willing, and interested to participate in clinical research. It may be speculated that this snapshot represents the less severe and more engaged population of the DM1 population in the UK. However, it could be argued that more severely affected patients may engage more with research as there is a greater impact on their daily lives. The reliability of the patient-reported symptoms such as myotonia could also be questioned as these terms may not be accurately understood by patients, this may be a specific concern in DM1 considering the cognitive impairment present in many. However, a limited compliance check across three centres showed the reliability of patient-reported data to be very promising, validating the move towards an increase in self-reported outcomes. Furthermore, evidence suggests that patients gain additional benefit from this level of engagement [
25].
Clinical and genetic information is not available for some patients; this is due to some delays in obtaining local R&D approvals and the burden on the professional’s time. Without full integration into the healthcare system or provision of resources at a larger scale it may not be possible to capture complete genetic and clinical information on all patients.
To improve the completeness of the data a larger proportion of the data items could be completed by the patient themselves, particularly relating to the age at onset and questions regarding medications and ventilation. Having more information about how many patients have tried a treatment but failed to tolerate it could help to improve current best practice and warrant future investigation.
Clinical lessons and hypothesis generation
The registry has already helped to formulate hypothesis for future studies which may lead to better understanding of the condition. For example, the data presented support a recent study indicating gender differences in DM1 [
8]. Similar to this study, men had higher frequencies of severe myotonia, mobility impairments, cardiac abnormalities, and non-invasive ventilation, whereas women presented more often with cataracts. Contrasting the results of Dogan et al., the frequency of patients with dysphagia was slightly higher in men than in women. We additionally found significantly more severe fatigue among female DM1 patients, which has not been described before. Although the symptoms in Dogan et al. were professional reported [
8], many of the gender differences were confirmed by our patient-reported data in an independent population.
The most prevalent symptom described in the registry is fatigue and excessive daytime sleepiness, known to also be one of the most disabling leading to disability, unemployment, family breakdown, and reduced quality of life [
26,
27]. Clinical reports and small studies suggest that stimulating drugs such as modafinil may have a profound, positive effect on excessive daytime sleepiness and quality of life in DM1 patients [
6,
22,
26]. However, after review by the European Medicines Agency it was recommended that due to lack of evidence [
28] its use in myotonic dystrophy should be ceased. However, the unmet medical need for treatment for fatigue remains strong and potentially new molecules like pitolisant or other stimulant drugs [
29], may offer room for future trials seeking innovative solutions for this prevalent symptom.
A correlation between dysphagia and myotonia has been observed in the registry data, with dysphagia occurring more frequently in patients who also report myotonia. This positive correlation is also seen between myotonia and mobility impairment. This is contradictory to the authors’ clinical impression that dysphagia is associated with muscle weakness and is negatively correlated with myotonia. Further clinical investigation may allow us to understand these findings as they could impact care and treatment.
The data presented suggest that there is a significant delay between symptom onset and genetic diagnosis [
30]. This has been shown in other cohorts and suggests a need to adopt better guidelines for the identification and diagnosis of DM1. There is rapid progress in the development of new targeted treatments such as antisense oligonucleotide therapies [
14‐
16] and while these studies are treated with appropriate caution, they highlight the need for detailed genetic information in order for this community to be not only “trial-ready” but also “treatment-ready”. Furthermore, delays in diagnosis prevent the best care being provided to patients, such as existing approaches for monitoring cardiac function and symptomatic treatments for fatigue and myotonia. Genetic testing for DM1 by Southern blot analysis of restriction digested genomic was introduced into the UK in the early 1990s shortly after the identification of the gene in 1992 [
9‐
11]. A move was made to triplet-primed PCR after this method was described in 1996 [
31]. Our data do not show a reduction of the diagnostic gap in the last 20 years. This suggests that the delay in genetic diagnosis is not due to availability of a genetic test but to other factors. Consideration should be given to assessing the reasons for the delay and the impact this has on patient care and quality of life.
Our data regarding diagnosis could be improved with better characterisation of age of onset and inclusion of presenting symptom. This could help better understand if certain symptoms such as bowel dysfunction (information about which is not currently collected), cataracts, or excessive daytime sleepiness may not be picked up as quickly as muscle weakness or grip myotonia as suggested by previous studies [
32,
33]. As most diagnostic laboratories in the UK use the repeat-primed PCR assay, CTG repeat lengths are not part of the diagnostic report, therefore these data are not readily available for most DM1 patients in the UK. This limits interpretation of genotype–phenotype correlations, the value of this should be considered by health care providers considering the potential added value in prognosis and standards of care.
Future considerations
The registry allows self-reported outcomes to be collected from a large cohort of patients with direct and ongoing access. The results shown here may inform the design of future academic studies into the pathophysiology of the condition and provide relevant information for clinical trials. The collection of longitudinal data over time will provide an additional resource when assessing the progression of the condition.
The common TREAT-NMD dataset is shared by at least 19 registries across 17 different countries (Argentina, Australia, Bulgaria, Canada, China, Czech Republic, Egypt, France, Germany, Italy, Japan, New Zealand, Poland, Serbia, Spain, UK and US). Ideally, all registries would be linked centrally by this common dataset allowing data to be shared across the research community. The TREAT-NMD Alliance has successfully established a global network of national registries for Duchenne muscular dystrophy and spinal muscular atrophy [
34,
35] and continues to play an active and important role in coordinating neuromuscular registries globally. The registry is aiming to be part of any future collaborative efforts by TREAT-NMD.
Increased harmonisation and collaboration not only between registries, but also across resources could enable communication between different health care systems in a sensitive and secure manner. This kind of collaboration and data sharing is key to understanding the natural history of these complex and rare diseases and there are number of initiatives in Europe currently looking at ways to achieve this, for example RD-Connect (
http://www.rd-connect.eu) [
17,
36].
The UK Myotonic Dystrophy Patient Registry is an example of a novel, online-based, cost-effective, and patient-driven registry. Its success can be measured by its continuous growth and utilisation. Although primarily designed to accelerate and facilitate trial recruitment and planning the registry has also provided and interesting and important data characterising the DM1 patient community in the UK.