Whole Exome Sequencing detects PYGM variants in two adults with McArdle disease

McArdle disease is a progressive and debilitating glycogen storage disease with typical onset in late childhood. Here we describe a former competitive athlete with early adult onset McArdle disease and a septuagenarian with a history of exercise-intolerance since adolescence who was evaluated for proximal muscle weakness. Exome sequencing identified bi-allelic variants in PYGM gene for both cases. The former athlete has the common, well-known pathogenic variant p.(Arg50Ter) in trans with a novel missense variant, p.(Asp694Glu). The second individual has a previously described homozygous missense variant, p.(Arg771Gln). Here, we describe the clinical course, enzyme-testing results using muscle tissue and molecular findings for the individuals, and add to the knowledge of the genotypic spectrum of this disorder.

Preclinical Research in McArdle Disease: A Review of Research Models and Therapeutic Strategies

McArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by pathogenic mutations in the PYGM gene, which encodes the skeletal muscle-specific isoform of glycogen phosphorylase. Clinical symptoms are mainly characterized by transient acute “crises” of early fatigue, myalgia and contractures, which can be accompanied by rhabdomyolysis. Owing to the difficulty of performing mechanistic studies in patients that often rely on invasive techniques, preclinical models have been used for decades, thereby contributing to gain insight into the pathophysiology and pathobiology of human diseases. In the present work, we describe the existing in vitro and in vivo preclinical models for McArdle disease and review the insights these models have provided. In addition, despite presenting some differences with the typical patient’s phenotype, these models allow for a deep study of the different features of the disease while representing a necessary preclinical step to assess the efficacy and safety of possible treatments before they are tested in patients.

The Second Wind in McArdle Patients: Fitness Matters

Background: The “second wind” (SW) phenomenon—commonly referring to both an initial period of marked intolerance to dynamic exercise (e.g., brisk walking) that is not followed by perceived improvement and disappearance of previous tachycardia (i.e., the actual “SW”) until 6–10 min has elapsed—is an almost unique feature of McArdle disease that limits adherence to an active lifestyle. In this regard, an increase in the workload eliciting the SW could potentially translate into an improved patients’ exercise tolerance in daily life. We aimed to determine whether aerobic fitness and physical activity (PA) levels are correlated with the minimum workload eliciting the SW in McArdle patients—as well as with the corresponding heart rate value. We also compared the SW variables and aerobic fitness indicators in inactive vs. active patients.Methods: Fifty-four McArdle patients (24 women, mean ± SD age 33 ± 12 years) performed 12-min constant-load and maximum ramp-like cycle-ergometer tests for SW detection and aerobic fitness [peak oxygen uptake (VO2peak) and workload and ventilatory threshold] determination, respectively. They were categorized as physically active/inactive during the prior 6 months (active = reporting ≥150 min/week or ≥75 min/week in moderate or vigorous-intensity aerobic PA, respectively) and were also asked on their self-report of the SW.Results: Both peak and submaximal indicators of aerobic fitness obtained in the ramp tests were significantly correlated with the workload of the SW test, with a particularly strong correlation for the VO2peak and peak workload attained by the patients (both Pearson’s coefficients > 0.70). Twenty (seven women) and 24 patients (18 women) were categorized as physically active and inactive, respectively. Not only the aerobic fitness level [∼18–19% higher values of VO2peak (ml⋅kg–1⋅min–1)] but also the workload of the SW tests was significantly higher in active than in inactive patients. All the inactive patients reported that they experienced the SW during walking/brisk walking in daily life, whereas active patients only reported experiencing this phenomenon during more strenuous activities (very brisk walking/jogging and bicycling).Conclusion: A higher aerobic fitness and an active lifestyle are associated with a higher workload eliciting the so-called SW phenomenon in patients with McArdle disease, which has a positive impact on their exercise tolerance during daily living.

A First Case Report Of Mcardle Disease And Alive Kidney Transplantation

McArdle disease (Glycogen storage disease type V, GSDV ) is an inherited disorder of glycogen metabolism affecting only skeletal muscles. A 56-year-old male patient with McArdle disease had the symptoms such as fatigue, muscle weakness since he was 8 years old in his history. A Pre-emptive kidney transplant from his wife was performed on the patient who has gone through rhabdomyolysis attacks during his life period. As far as known, this is the first case in the literature. We aim to share this process before and after the transplantation.