Improvement of Symptoms in a Patient With Glycogen Storage Disease Through Nutritional Guidance and Exercise Therapy

Abstract

McArdle disease (glycogen storage disease type V) is a rare metabolic disorder caused by a deficiency in muscle phosphorylase, which is encoded by the PYGM gene. This deficiency leads to impaired glycogen metabolism, resulting in exercise intolerance, muscle cramps, and stiffness. This report describes the case of a woman first diagnosed with McArdle disease at age 59 years with genetic testing. The patient experienced lifelong exercise-induced muscle symptoms, which improved through combined preexercise sucrose intake and mild-to-moderate aerobic exercise. Nutritional guidance and structured physical activity remarkably alleviated her symptoms and improved her life quality. The interventions also improved the patient's body composition and grip strength, enhanced exercise tolerance, and reduced fatigue during daily activities. These clinical improvements occurred without any worsening of glucose tolerance, contributing to a meaningful enhancement in the patient's life quality. This case underscores the importance of early diagnosis of McArdle disease and highlights the potential benefits of personalized comprehensive interventions including those targeting lifestyle factors like diet and exercise in clinical management of McArdle disease.

Introduction

McArdle disease (glycogen storage disease type V) is a disorder of carbohydrate metabolism first described by Brian McArdle in 1951, with an estimated prevalence of approximately 1 in 100 000 individuals. It is an autosomal recessive inherited disorder caused by mutations in the PYGM gene, which encodes the muscle-specific isoform of glycogen phosphorylase, leading to impaired glycogenolysis in skeletal muscle and resulting in exercise intolerance [1]. Individuals with McArdle disease typically experience exercise intolerance characterized by early fatigue and muscle contractures triggered by static muscle contractions such as weightlifting or dynamic activities like stair climbing and brisk walking; in some cases, this manifests as reversible acute crises accompanied by rhabdomyolysis and myoglobinuria [1]. Another distinguishing feature of this disorder is the phenomenon known as the “second wind.” This refers to a marked improvement in tolerance to aerobic activities such as walking or cycling after approximately 10 minutes of exercise, during which the initially triggered tachycardia and excessive fatigue subside [2].

This disease is rare and presents with nonspecific symptoms, making it difficult to diagnose and often leading to delayed identification. A definitive diagnosis is made through genetic testing, such as whole exome sequencing, which identifies pathogenic variants in the PYGM gene [1]. In addition, the nonischemic forearm exercise test—measuring lactate and pyruvate levels before and after exercise—can also be useful in assessing anaerobic metabolism and supporting the diagnosis [3].

Although no definitive treatment is available, some nutritional [4, 5] or exercise [6, 7] interventions can mitigate symptoms. This case report illustrates the successful management of McArdle disease through comprehensive approaches of nutritional and physical activities.

Case Presentation

A 59-year-old Japanese woman, born to consanguineous parents, presented with lifelong difficulties in performing physical activities, including running, pull-ups, and hopping. However, she had never sought medical attention. She experienced frequent muscle cramps and stiffness, especially under stress, but noted symptom relief with gradual activity continuation, consistent with the second-wind phenomenon.

Although her symptoms slightly improved in adulthood, routine examinations occasionally revealed elevated creatine kinase (CK) levels and mildly elevated liver enzymes, which reflect muscle damage, whereas abdominal ultrasound and computed tomography scans did not reveal any significant hepatic abnormalities.

Three years before presentation, her biological sister was diagnosed with McArdle disease following an episode of acute rhabdomyolysis, leading to the genetic testing, which confirmed a homozygous pathogenic variant in PYGM (stop gained c.148C > T [p.Arg50]). McArdle disease was therefore suspected, and the patient was referred to our hospital for further evaluation.

Diagnostic Assessment

Laboratory tests revealed elevated CK and liver enzyme levels, although urinalysis did not detect myoglobinuria (Table 1). A nonischemic forearm exercise test demonstrated no postexercise lactate or pyruvate increases, consistent with McArdle disease. In contrast, following a previous report [4, 5], administering a 37-g sucrose load resulted in significant elevations in lactate and pyruvate levels, accompanied by symptomatic improvement (Fig. 1). Genetic testing revealed the same homozygous pathogenic variant in PYGM (stop gained: c.148C > T [p.Arg50]) as her sister, confirming the diagnosis of McArdle disease.

Table 1.

Laboratory findings summary

Biochemistry	Value	Reference range
Creatine kinase	400 IU/L	41-153 IU/L
Aspartate aminotransferase	31 IU/L	13-30 IU/L
Alanine aminotransferase	30 IU/L	7-23 IU/L
Lactate dehydrogenase	236 IU/L	124-222 IU/L

Figure 1.

Results from the sucrose load and exercise tests. (A) Lactic acid and pyruvic acid. (B) CK and ammonia in a nonischemic forearm exercise test and a 37-g sucrose load test. The nonischemic forearm exercise test demonstrated no postexercise lactate or pyruvate increases, consistent with McArdle disease. The dashed line represents the condition without sucrose loading, while the solid line indicates the condition with 37-g sucrose loading.

Treatment

In the nonischemic forearm exercise test, an improvement in exercise tolerance was observed following sucrose intake. This suggests that sucrose intake efficiently provided exogenous glucose, bypassing the impaired glycogenolysis pathway and directly supplying energy for muscle activity. Thus, a high-carbohydrate diet with a carbohydrate ratio of 65% was advised. Additionally, she was advised to consume sugar before exercise to provide an alternative energy source, based on her personal daily activity profile. Concerns about a rapid blood glucose elevation from the occasional intake of sugar alone led to the recommendation to consume protein before sucrose intake, which is also considered to prevent sarcopenia. Specifically, she ate sweet breads frequently and had insufficient protein intake before admission. Therefore, we advised her to eat plain bread or approximately 180 g of cooked rice and to add protein such as a boiled egg or soy products. She was physically active after breakfast, such as during her commute, so we recommended adding sucrose to her morning milk. Initially, the patient consumed 37 g of sucrose (0.67 g/kg body weight), based on previous reports [4, 5] and its demonstrated efficacy in the nonischemic forearm exercise test. To minimize the potential impact on glucose tolerance, the sucrose dose was gradually reduced. Symptomatic improvement during exercise was observed even with 26 g (0.47 g/kg body weight), and therefore, the patient is currently maintained on a 26-g sucrose load.

Concomitantly, physical function was assessed by a physical therapist at the time of hospital admission and we encouraged moderate aerobic activities, such as walking 10 000 steps per day, with a target heart rate of approximately 100 bpm (60%-70% of her maximum heart rate), while avoiding high-intensity isometric exercises.

Vitamin B6 is a coenzyme for muscle-type glycogen phosphorylase, and a report showed supplementation with vitamin B6 possibly improved enzyme activity and alleviated exercise symptoms in some Japanese patients with McArdle disease [8]. So, based on previous reports [8], we also started vitamin B6 supplementation (60 mg/day; 1.1 mg/kg body weight).

Outcome and Follow-up

The follow-up dietary interview conducted by a registered dietitian revealed that she ate approximately 240 g of carbohydrates (60%) and 71.5 g of protein (18%) per day. At first, she was able to follow the dietary recommendations in her routine about 60% of the time. Over time, as the changes became more familiar, her adherence improved to around 80% to 90% at 3 months after discharge. Following the combination of nutritional and exercise therapy, the Visual Analog Scale for pain score, which was 6 to 7/10 before treatment, improved to 0/10, showing significant symptom improvement and enhanced life quality. Three months after starting treatment, as shown in Table 2, handgrip strength tended to increase. Body fat mass and body mass index decreased, whereas skeletal muscle mass remained stable, suggesting that muscle mass and strength were preserved. (Table 2). Regular follow-ups demonstrated stable CK levels, remaining around 250 IU/L, with liver enzymes also stable, and continued adherence to dietary and exercise recommendations without adverse effects. Given that preexercise sucrose ingestion and high-carbohydrate diets may potentially impair glucose tolerance, periodic follow-up was performed in accordance with previous recommendations [9]. We conducted monthly nutritional counseling and blood tests every 3 months, during which no deterioration in hemoglobin A1c was observed.

Table 2.

Result of changes in grip strength, body composition, HbA1c, and fasting plasma glucose level over 3 months

	Grip strength (Rt/Lt)	Skeletal muscle mass	Fat mass	BMI	Visual analog scale	HbA1c	Fasting plasma glucose
On admission	14.5/13.3 kg	18.0 kg	20.4 kg	24.3 kg/m2	6-8	5.8%	91 mg/dL (5.1 mmol/L)
1 month later	16.4/17.0 kg	18.4 kg	19.8 kg	24.1 kg/m2	0	5.8%	63 mg/dL (3.5 mmol/L)
2 months later	16.7/17.0 kg	18.6 kg	18.8 kg	23.9 kg/m2	0	—	—
3 months later	16.2/14.7 kg	18.7 kg	18.8 kg	23.9 kg/m2	0	5.9%	97 mg/dL (5.4 mmol/L)

Grip strength was measured without sucrose loading. Skeletal muscle mass and body fat mass were measured using the InBody 720, which uses impedance measurement. The Visual Analog Scale represents the degree of pain experienced during daily activities and exercise.

Abbreviations: BMI, body mass index; HbA1c, hemoglobin A1c; Lt, left; Rt, right.

Discussion

McArdle disease is a disorder of carbohydrate metabolism of skeletal muscle caused by a deficiency of muscle-specific glycogen phosphorylase, resulting in impaired glycogen breakdown and insufficient adenosine triphosphate production required for muscle contraction. It is a rare disorder, and diagnosis is often challenging because of its nonspecific clinical manifestations. Indeed, a report from the United Kingdom indicated that the diagnosis of McArdle disease was delayed by an average of 29 years, with 90% of cases initially misdiagnosed as “growing pains” or “laziness,” sometimes resulting in unnecessary invasive tests or treatments [10]. Thus, misdiagnosis is a significant factor contributing to diagnostic delay, and early diagnosis is critically important because it promotes better understanding of the disease, acquisition of self-management skills, and prevention of rhabdomyolysis. In this case, our patient experienced muscle cramps and stiffness during physical activity from childhood and had difficulty with physical activities in daily life for more than 50 years. However, it was misunderstood by the patient and those around her, including her family, that the symptoms were just due to her mental and motor skills. Actually, she and her family did not seek medical attention even with persisting symptoms and her low self-esteem. The diagnosis was not made until her sister was diagnosed with McArdle disease. Limited awareness of the disease may not only prolong physical and psychological suffering but also increase the risk of severe complications such as rhabdomyolysis, resulting from inappropriate medical interventions or the imposition of excessive physical exertion.

As a therapeutic approach, sucrose intake has been shown in several previous studies to be effective as a method of efficiently providing exogenous glucose and directly supplying energy for muscle activity [4, 5, 11]. In this case, an increase in lactate and pyruvate levels was observed during the nonischemic forearm exercise test after sucrose intake, suggesting an increase in anaerobic metabolism. Therefore, sucrose intake before exercise was considered effective for addressing the muscle symptoms in this case and occasional sucrose intake was encouraged based on her personal daily activity profile. Additionally, a high-carbohydrate diet with a carbohydrate ratio of 65% has been reported to improve exercise symptoms by maintaining liver glycogen stores [12]. Thus, the patient was also advised to follow a diet with approximately a 65% carbohydrate ratio. Although effective, occasional sucrose intake and a daily high-carbohydrate diet must be balanced against their potential metabolic risks like weight gain and glucose fluctuations. It has been stated that in individuals with reduced insulin sensitivity, carbohydrate-rich diets should be administered with caution [12]. Regarding sucrose intake, if the caloric intake exceeds energy expenditure, it may lead to weight gain; therefore, sucrose intake should be limited to preexercise consumption [4]. Furthermore, previous studies have also reported that consuming sucrose during exercise does not improve exercise tolerance [13]. Based on these findings, sucrose intake in this case was restricted to the preexercise period. In this case, in addition to limiting sucrose intake to preexercise, the patient was advised to consume protein before sucrose intake to prevent sarcopenia and mitigate the rapid increase in blood glucose levels.

Exercise therapy is also crucial in symptom management. Moderate-intensity aerobic exercise has been shown to be well-tolerated and, when performed regularly, significantly increases the work capacity of individuals with McArdle disease [6]. Therefore, we encouraged moderate-intensity aerobic exercise following sucrose intake.

By combining personalized comprehensive nutritional and exercise therapy, the patient's exercise-induced pain disappeared, allowing her to perform daily activities without discomfort. Consequently, the patient's daily physical activity increased, leading to the maintenance of muscle strength with a trend toward improvement in grip strength. Furthermore, by consuming protein before sucrose intake and after aerobic exercise, no significant weight gain or deterioration in glucose tolerance was observed. Although few reports showed the clinical outcomes of combined nutritional and exercise therapy in McArdle disease, this case demonstrated a successful therapeutic strategies for McArdle disease; the personalized combination of nutritional and exercise therapy. Further investigation to establish optimized treatment strategies is warranted considering the potential high degree of individual variability. Moreover, long-term follow-up is warranted to evaluate the durability of symptomatic improvement and to ensure the metabolic safety of the intervention.

In addition to nutritional and exercise therapy, vitamin B6 was administered in this case. Vitamin B6 is a coenzyme for muscle-type glycogen phosphorylase, and a report showed supplementation with vitamin B6 possibly improved enzyme activity and alleviated exercise symptoms in a limited number of Japanese patients with McArdle disease [8]. However, the genetic mutation identified in this case was a null mutation, commonly observed in Caucasians [14], and the effectiveness in this case is considered to be limited [8]. Therefore, depending on the future progression, discontinuation of the supplementation may be considered.

In conclusion, this report highlights diagnostic delay of McArdle disease in the real clinical settings. Nutritional and exercise therapy should be tailored to the patient's activity level and symptom severity. In this case, the personalized combination of nutritional and exercise therapy such as occasional preexercise protein and sucrose intake, daily high-carbohydrate diets, and daily moderate-intensity aerobic exercise improved the symptoms without inducing obesity and worsening glucose intolerance.

Learning Points

• McArdle disease is a rare metabolic disorder characterized by exercise intolerance, muscle cramps, and the second-wind phenomenon.

• Preexercise sucrose intake can alleviate symptoms by providing an alternative energy source.

• Moderate-intensity aerobic exercises improve exercise tolerance while minimizing muscle damage.

• Consultation with a registered dietitian and an exercise physiologist is valuable for introducing specific dietary and physical activity recommendations, as well as for monitoring patient compliance and identifying challenges to these recommendations.

• A personalized approach to nutrition and exercise is essential for optimal symptom management.

Contributors

All authors made individual contributions to authorship. All authors were involved in the diagnosis and management of this patient. T. Morita, T. Murakami, and E.O. were involved in writing the first draft and submission. S.I. was involved in the management of this patient, including the provision of nutritional counseling. M.M. was responsible for data analysis and preparation of the first draft of the manuscript and contributed to subsequent revisions. T. Murakami and D.Y. supervised the study, revised the manuscript critically for important intellectual content, and approved the final manuscript. All authors reviewed and approved the final draft.

Funding

No public or commercial funding was received for this case report.

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent obtained directly from patient.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analyzed.