Data from the European registry for patients with McArdle disease (EUROMAC): functional status and social participation

Glycogen storage disease type 5, GSD5 (McArdle disease) is a rare metabolic myopathy with a prevalence of approximately 1:100,000 [1]. It is caused by inherited deficiency of muscle glycogen phosphorylase, also known as myophosphorylase. GSD5 is characterized by physical activity intolerance manifesting as muscle fatigue, cramping and pain, during vigorous activities [1]. If continuing activity at the same intensity, individuals are at risk for rhabdomyolysis and myoglobinuria [2]. GSD5 is rare and has an autosomal recessive inheritance pattern and a variable presentation. As a consequence, many participants experienced a long diagnostic delay [4]. This is expected to improve with the wide availability of diagnostic next-generation sequencing [31]. Once diagnosed, symptomatic treatment is often not provided.

The European registry for individuals with GSD5 and other muscle glycogenosis (EUROMAC) was launched to raise awareness of diagnostic accuracy of muscle GSDs, improve care, and collect important clinical and epidemiological data for use in future clinical trials by Scalco et al. [3, 4] The first two EUROMAC reports focused on the design of the registry and the clinical and genetic characteristics and comorbidities. The main findings were a high frequency of fixed weakness, normal CK values in a minority of participants, body mass index above background population and a high prevalence of hypothyroidism and coronary heart disease. [3, 4] We here present the additional data collected in the EUROMAC registry, including scores on social participation, previous and current treatments, functional limitations, fatigue, health disability, quality of life and physical activity.

The EUROMAC registry was created to ensure data collection and its maintenance with the aim to improve diagnosis and care for individuals with rare glycogen storage diseases. The registry increases knowledge from clinical data from individuals with GSD5 and related conditions and has played a positive role in promoting translational research [3]. Moreover, it is one of few international registry of muscle glycogenosis available. Besides unraveling phenotypic characteristics of GSD5 as seen in the accompanying papers [3, 4], the current report provides insight in the previous treatments, functional limitations, fatigue, health disability, quality of life and physical activity. We will discuss the main findings below.

The number of participants currently working (67%) is in line with the proportion of the general adult population that is working in various European countries: 72% in the Netherlands [13], 76% in the UK [25], and 66% in Spain [26]. This normal labor force participation rate might be related to the reported adaptations: 29% had changed their job and 22% had their work environment modified. Reported physical activity during work is variable, including sitting and non-sitting labor.

In line with previous studies, many participants reported use of medication to relieve pain. Both over the counter and prescribed drugs were used, mostly paracetamol (acetaminophen). Paracetamol is unlikely to relieve acute muscle pain but may be taken to manage more severe pain, which may last for hours after exercise [14]. Furthermore, 26% of participants reported opioid medication in combination with other analgesic drugs. This is not recommended, as these drugs may mask feedback from muscles, leading to further muscle damage and recurring pain [14]. The recently published Clinical Practice Guidelines recommend a regular exercise program as a safe manner to reduce chronic pain [14‐17]. Other drugs commonly used are psychoactive drugs (18% compared to 5.5% in general population) and cardiovascular drugs (17% compared to), which make sense since a high rate of coronary heart disease was described in the EUROMAC paper [4]. For comparison, 10.7% of U.S. adults used one or more prescribed pain medications in the past 30 days; 13% of males use over the counter analgesics weekly and 11.9% of US adults reported having used opioids in the past 12 months (data mainly from USA, 2015–2018) [32‐34].

Most of the participants who used a sucrose supplementation and carbohydrate rich diet found it beneficial. The beneficial effects of oral sucrose supplementation before exercise are well established [14, 19, 29]. Also, a carbohydrate rich diet has shown to attenuate muscle pain in the first few minutes of exercise before the second wind compared to a protein rich diet and has proven beneficial because it maintains the hepatic glycogen stores [14, 20, 21]. Both the protein-rich and the lipid-rich diet were reported as not beneficial for our cohort but only by a low sample size. Still, improvement in parameters for the sucrose supplementation and carbohydrate rich diet need to be studied since none indicated significant clinical benefits.

In the open-questions the ketogenic diet was reported as beneficial. Other studies that have investigated the effects of a modified ketogenic diet in individuals with GSD5 and one informal survey showed improvement in symptoms and exercise tolerance for most of the cohort after using the ketogenic diet. [22, 23] The BCAA supplementation was found beneficial for 67% but since only 3 participants have used it, not much can be concluded.

The reported rehabilitation programs are in line with recommended physical and occupational therapy. Remarkably, 60% of the participants reported walking as an important rehabilitation approach. The international patient support group IamGSD has promoted walking as a training for GSD5 for years [24]. Also, walking can easily be implemented in daily life. Future research could focus on objectively demonstrating the positive effect of walking and other forms of aerobic exercise in daily life. The inclusion of participants in the registry may have resulted in a higher proportion of individuals who are more active, presumably both mentally and physically, as they actively seek medical assistance. However, caution should be exercised due to the potential overestimation of rehabilitation use stemming from selection bias.

Moreover, for comparison of fatigue, the FSS score for individuals with Lyme disease is 4.8, Parkinson’s disease is 4.1 and for a healthy population it is 2.3. [11, 12, 30]

Limitations of this study include the collection of retrospective data and the issue of missing data, which reduces the validity. The data was collected in the prospective EUROMAC registry and had to be entered by various researchers and clinicians. This carries the risk of observation or confirmation bias in case of subjective outcome measures. The data from the WHODAS was not of sufficient quality to be interpreted further. It is also important to note that the present study had a limited number of correlation analyses, which may restrict the generalizability of the findings and the ability to explore potential relationships between additional variables of interest. Furthermore, to have researchers and clinicians enter the patient-reported outcome measures scores was challenging. It has led to missing data and implies propensity to error. Prospective patient registries where patient-reported outcome measures (PROMS) are completed by patients themselves are expected to have a better validity [27, 28]. Nevertheless, the EUROMAC has raised awareness of diagnostic accuracy and collected important data for use in future clinical trials with the accompanying papers [3, 4].

The EUROMAC registry helps to gain more understanding of GSD5. It provides inspiration for other clinicians to develop patient registries for other rare diseases. The analyses in this paper has given insight into the functional limitations and treatments and rehabilitation approaches used. The findings support the recent international recommendations for people with GSD5, including adopting an active, healthy lifestyle and careful use of analgesic drugs. Moreover, participants that used diet and supplementation mentioned beneficial effects. This can be promising, however placebo-controlled studies with larger cohorts are warranted to provide conclusive evidence of the effects of these diets and supplementations.