Creation and implementation of a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC registry)

McArdle disease (glycogen storage disease type V, myophosphorylase deficiency) is an autosomal recessive disorder of glycogen metabolism, originally described in 1951 [1]. It is the most frequent metabolic myopathy with an estimated prevalence of ~ 1 in 140,000 people [2]. The disease is caused by mutations in PYGM that encodes the muscle isoform of glycogen phosphorylase (GP-MM; 1,4-alpha-D-glucan: phosphate alpha-D-glucosyltransferase). The mutations lead to loss of enzyme activity and thus inability to break down muscle glycogen, making this source of energy unavailable to patients [3]. Clinically, McArdle Disease is characterized by exercise intolerance typified by acute crises of early fatigue and muscle contractures that in ~ 50% of the cases are accompanied by rhabdomyolysis, hyper-creatine kinase (CK)-emia and myoglobinuria, which occasionally result in acute renal failure [3, 4]. In case of delayed diagnosis and incorrect medical advice, this could lead to risk of life-threatening crises necessitating admission to critical care. There is phenotypic variability, ranging from rare cases of patients that are virtually asymptomatic to the more common ones reporting recurrent exertional myoglobinuria, fixed muscle weakness and severe limitations of exercise and most daily life activities [2, 5].

There are scarce data available on the McArdle Disease epidemiology, as most of the studies have been limited by small sample sizes, consistently < 100 cases [4, 6‐20]. The study of large cohorts of patients with rare disorders such as McArdle Disease is hampered by the low prevalence and heterogeneity of patient populations, as well as by the limited knowledge of their natural history. The largest cohort of McArdle Disease patients was reported in 2012, which described the features of 239 Spanish patients [5], updated 5 years later with 94 additional patients [2]. Studies of larger cohorts are clinically important as they help to improve our knowledge about the disease and of the main problems faced by patients, thereby allowing for targeted lifestyle intervention. Thus, the European Commission and the National Institutes of Health have set-up international patient registries for rare diseases to facilitate knowledge about them and to promote better standards of care and diagnosis.

We aimed to implement a European Patient Registry for McArdle Disease and other rare muscle glycogenoses (EUROMAC registry, EMR). The present paper describes how the EMR was developed and implemented detailing its strengths and shortcomings with the aim of facilitating the creation of other rare disease patient registries.

EMR is an entirely public and secure database designed to contain the medical data from patients with McArdle Disease and related conditions. The EUROMAC network collaboration was initiated in 2012 with the main objective of improving diagnosis and care for people living with these rare disorders, to reduce serious complications and social care costs and to provide a research platform for future clinical trials by raising awareness and increase knowledge with respect to the natural history of these disorders. In patients with these disorders, delayed diagnosis and incorrect medical advice leads to debilitating symptoms and increased risk of life-threatening crises necessitating admission to critical care, all of which can be prevented by correct medical care. The EUROMAC was a complex undertaking that involved multi-disciplinary teams of 18 partners from nine countries. Owing to the low number of patients with rare muscle glycogenolytic disorders at national level, the EUROMAC registry was created at European level establishing collaborative efforts to ensure data collection and its maintenance.

To date, the project fulfilled the expectations for an accessible and readily visible e-platform where the scientific community can count and properly describe most patients with rare muscle glycogenoses. Registration of the patients proceeded steadily once the registry functions were in place, reaching the number of 313 by November 2019. The choice of enriching the registry with a wealth of clinical and functional information makes the registry, in its present form, a good starting point for a dynamic specialized e-health record, but is also the main reason for its underperformance in number of registered patients. Although the initial expectations for registering rate were higher than those actually achieved (the initial target was having 500 registered patients at the end of the CHAFEA-funded period), this number had to be lowered to a more realistic value (250 patients) in one of the interim amendments of the project. Indeed, when the consortium started registering patients, it was soon detected that efficiency in loading the patients’ data was below initial expectations because of the need to obtain a signed consent form from each subject, which was the main rate-limiting factor. Moreover, the richness of the clinical information required, which demanded for direct patient re-examination for most of the requested measures, also added to the delay in registration, which is still on going. This element is confirmed by the unequal speed and number of data entry by the various partners: those who have routine scheduled visits of the patients could easily retrieve the needed data, those performing diagnostic workout but no clinical follow-up could not keep up. Taken together, we assumed that lowering the initial registering activity rate expectations was fully justified if that allowed that the quality of the data (and so the usefulness of the registry) is more robustly ensured.

In addition to the scientific observations and conclusions derived from data analysis, presented in the companion paper [21], when we look to what we learned from the registering activity from a methodological and procedural point of view, we can raise the following conclusions:

Additionally, the expected long-term impacts of the EUROMAC project at an international level are: a) improved access of patients to specialised care; b) facilitated involvement of national governments and regulatory agencies; c) improved knowledge of the natural history of McArdle Disease and other rare muscle glycogenoses; d) reduced average delay in diagnosis; e) reduced risk of incorrect advice leading to debilitating symptoms and increased risk of life-threatening crises; and f) extended use of the registry to all other European countries. All these long-term expected impacts will need further analyses after extended time of registering patients.

The project has also contributed to the establishment of a communicative channel with the biopharmaceutical industry, because the registry will improve the understanding of the natural history of these diseases, and the available data enables designing better clinical trials and evaluating potential relevant clinical endpoints.

A positive aspect of the project is the dissemination and the raised awareness about this neglected group of rare diseases. The power of a dedicated multilingual web site and the possibility for patients to directly contribute was hailed by most patients as a very positive novelty. The distribution of multilingual information material on McArdle Disease is a concrete achievement that will continue beyond the project life. Over 90% of the patients contacted for first data collections were happy to be contacted again for follow-up. Participation by consortium partners to all meetings forged a strong sense of belonging among the partners, which functioned as accretion nucleus, leading other European partners to join the consortium (Netherland and Poland). Actually, incorporation of new active EUROMAC partners has been encouraged and welcome by the initial EUROMAC consortium, among those participants that have joint as registering professionals following the mechanism described in the Methods and Results section above (Data collection, storage, and access policy), when they show interest to become active participating partners. The training sessions held in London and Madrid, as well as the workshop held in Naarden [23], achieved the double goal of standardizing assessment procedures and increase knowledge on specific functional and clinical aspects of the diseases. They were attended by a large number of professionals and were rated by participants as very useful and qualitatively excellent. In addition, special efforts dedicated to disseminate our project in Eastern countries, with meetings held in Warsaw and Belgrade, have contributed to increase knowledge and awareness about these disorders in Eastern Europe. We expect that these dissemination strategies will contribute to improve diagnosis of these diseases in this region, where underdiagnose of these diseases seems to be of special concern.

In conclusion, EMR represents a major step forward in the knowledge of muscle glycogenoses with relevant clinical outcomes at the diagnostic, epidemiologic, clinical and research levels.