Exercise intolerance in Glycogen Storage Disease Type III: Weakness or energy deficiency?

doi:10.1016/j.ymgme.2013.02.008

Molecular Genetics and Metabolism

Volume 109, Issue 1, May 2013, Pages 14-20

https://doi.org/10.1016/j.ymgme.2013.02.008 Get rights and content

Abstract

Myopathic symptoms in Glycogen Storage Disease Type IIIa (GSD IIIa) are generally ascribed to the muscle wasting that these patients suffer in adult life, but an inability to debranch glycogen likely also has an impact on muscle energy metabolism. We hypothesized that patients with GSD IIIa can experience exercise intolerance due to insufficient carbohydrate oxidation in skeletal muscle. Six patients aged 17–36-years were studied. We determined VO_2peak (peak oxygen consumption), the response to forearm exercise, and the metabolic and cardiovascular responses to cycle exercise at 70% of VO_2peak with either a saline or a glucose infusion. VO_2peak was below normal. Glucose improved the work capacity by lowering the heart rate, and increasing the peak work rate by 30% (108 W with glucose vs. 83 W with placebo, p = 0.018). The block in muscle glycogenolytic capacity, combined with the liver involvement caused exercise intolerance with dynamic skeletal muscle symptoms (excessive fatigue and muscle pain), and hypoglycemia in 4 subjects. In this study we combined anaerobic and aerobic exercise to systematically study skeletal muscle metabolism and exercise tolerance in patients with GSD IIIa. Exercise capacity was significantly reduced, and our results indicate that this was due to a block in muscle glycogenolytic capacity. Our findings suggest that the general classification of GSD III as a glycogenosis characterized by fixed symptoms related to muscle wasting should be modified to include dynamic exercise-related symptoms of muscle fatigue. A proportion of the skeletal muscle symptoms in GSD IIIa, i.e. weakness and fatigue, may be related to insufficient energy production in muscle.

Highlights

► Metabolism during exercise and exercise tolerance were examined in the patients. ► The peak oxidative capacity was abnormally low. ► Exercise intolerance with excessive fatigue was evident in the patients. ► However, a glucose infusion significantly improved exercise capacity. ► GSD type IIIa thus includes dynamic exercise-related symptoms of muscle fatigue. ► This is due to insufficient energy production in skeletal muscle during exercise.

Introduction

Glycogen Storage Disease Type III (GSD III) is an inborn error of metabolism, which is caused by glycogen debranching enzyme (GDE) deficiency [1], [2]. GDE is expressed in most tissues and plays a central role in glycogen catabolism [3], [4]. In 85% of patients with GSD III, the GDE activity is absent in both skeletal muscle and liver (GSD IIIa) while 15% of patients have only liver involvement (GSD IIIb) [5], [6].

Skeletal muscle glycogen is an essential source of energy to support muscle contraction, especially at high intensities of exercise [7], [8]. Due to the defect in muscle glycogen breakdown in GSD III, it could therefore be expected that exercise-related symptoms occur in patients with GSD III, due to an energy crisis in muscle, similar to what is observed in myophosphorylase deficiency (McArdle disease, GSD V). The forearm exercise test has been used to examine exercise tolerance in patients with GSD III. However, exercise tolerance to more prolonged aerobic types of exercise involving larger muscle groups, has not yet been quantified in an experimental setting in patients with GSD III [9], [10].

The aim of the present study was to determine the response and tolerance to exercise in patients with GSD IIIa without major permanent muscle weakness. We questioned the current description of this disorder as being mainly associated with static muscle involvement in adults [9], [11], [12]. We hypothesized that in young patients with GSD IIIa, without major weakness or muscle wasting, we would observe exercise intolerance, as a consequence of an impaired skeletal muscle glycogenolytic capacity. In an attempt to unmask skeletal muscle metabolic derangements, we provoked muscle metabolism with moderate- and high-intensity exercise.

We determined peak work capacity on a cycle-ergometer, and the response to static forearm exercise. We observed whether or not a second-wind phenomenon occurred, and measured pulmonary gas-exchange, and plasma metabolites and hormones during cycle-ergometer exercise at 70% of VO_2peak (peak oxygen uptake). Finally, in an attempt to circumvent the metabolic block in skeletal muscle, the patients were allocated to receive either saline (placebo) or a glucose infusion during constant load cycling. This test was performed because we hypothesized that supplying energy below the metabolic block could improve exercise tolerance, as it has been observed in GSD V, which is similar in that the enzyme deficiency affects glycogenolysis [13].

Section snippets

Subjects and methods

Please refer to the Supplemental Data for additional details of the methods.

Peak exercise capacity

The VO_2peak was significantly lower in the patients (25.4 ± 5.1 mL/kg/min) compared to the healthy subjects (46.4 ± 7.2 mL/kg/min) (95% CI, − 28.1 to − 14.0, p = 0.001), as was the absolute oxygen uptake (Supplemental Table 1A). In accordance, the peak workload was significantly lower in the patients with a W_peak of 108 ± 27 versus 209 ± 55 in the healthy subjects (95% CI, − 152 to − 50, p = 0.001). The rise in blood lactate was severely blunted after peak exercise, indicating an almost complete block in

Discussion

In the present study, we examined and quantified exercise tolerance in adult patients with GSD III. We showed that GSD III is associated with dynamic exercise-related symptoms. In addition, we demonstrated that in 5 out of 6 patients, the clinical symptoms and biological anomalies that developed during exercise were improved by glucose infusion. Previous descriptions of the GSD III phenotype have mainly emphasized on the permanent muscle weakness and atrophy, which generally occur during the

Acknowledgments

The authors thank Dr. Karim Wahbi for the cardiac investigations and François Renard for the technical assistance.

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Physical therapy assessment and whole-body magnetic resonance imaging findings in children with glycogen storage disease type IIIa: A clinical study and review of the literature
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Early recognized manifestations of GSD III include hypoglycemia, hepatomegaly, and elevated liver enzymes. Motor symptoms such as fatigue, muscle weakness, functional impairments, and muscle wasting are typically reported in the 3rd to 4th decade of life.
In this study, we investigated the early musculoskeletal findings in children with GSD IIIa, compared to a cohort of adults with GSD IIIa.
We utilized a comprehensive number of physical therapy outcome measures to cross-sectionally assess strength and gross motor function including the modified Medical Research Council (mMRC) scale, grip and lateral/key pinch, Gross Motor Function Measure (GMFM), Gait, Stairs, Gowers, Chair (GSGC) test, 6 Minute Walk Test (6MWT), and Bruininks-Oseretsky Test of Motor Proficiency Ed. 2 (BOT-2). We also assessed laboratory biomarkers (AST, ALT, CK and urine Glc4) and conducted whole-body magnetic resonance imaging (WBMRI) to evaluate for proton density fat fraction (PDFF) in children with GSD IIIa. Nerve Conduction Studies and Electromyography results were analyzed where available and a thorough literature review was conducted.
There were a total of 22 individuals with GSD IIIa evaluated in our study, 17 pediatric patients and 5 adult patients. These pediatric patients demonstrated weakness on manual muscle testing, decreased grip and lateral/key pinch strength, and decreased functional ability compared to non-disease peers on the GMFM, 6MWT, BOT-2, and GSGC. Additionally, all laboratory biomarkers analyzed and PDFF obtained from WBMRI were increased in comparison to non-diseased peers. In comparison to the pediatric cohort, adults demonstrated worse overall performance on functional assessments demonstrating the expected progression of disease phenotype with age.
These results demonstrate the presence of early musculoskeletal involvement in children with GSD IIIa, most evident on physical therapy assessments, in addition to the more commonly reported hepatic symptoms. Muscular weakness in both children and adults was most significant in proximal and trunk musculature, and intrinsic musculature of the hands. These findings indicate the importance of early assessment of patients with GSD IIIa for detection of muscular weakness and development of treatment approaches that target both the liver and muscle.
Glycogen and polyglucosan storage diseases
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Glycogen is stored in the liver to maintain blood sugar in between meals. Muscles also store glucose, indeed they contain most of the glycogen in the body, to fuel the muscle function but muscles cannot share it with other tissue, because they lack the glucose-6-phosphatase. Absence of glycogen can be tolerated in children and adults as long as hypoglycemia is kept under strict control. Glycogen synthesis requires glycogen synthase and branching enzymes. Absence of glycogen branching enzyme or very active glycogen synthase makes a longer glucose chain that cannot be synthesized or degraded as efficiently causing the accumulation of abnormal glycogen. This condition is named glycogen storage disease type IV, which has different variants according to the remaining enzyme activity. Blocks in glycolysis or factors increasing glycogen synthase activity also cause polyglucosan or normal glycogen accumulation. Although the exact mechanism is not known, unbranched glycogen accumulates in the deficiency of ubiquitin ligases such as Malin, RBCK1, or phosphatase Laforin. Malin or Laforin deficiency causes very severe Lafora disease. Patients show the symptoms of the disease at 15 years of age and they die in a decade because of the severe epilepsy. On the other hand, RBCK1-deficient patients accumulate abnormal glycogen in muscle and heart, causing cardiopathy and myopathy.
Inborn Errors of Metabolism with Hypoglycemia: Glycogen Storage Diseases and Inherited Disorders of Gluconeogenesis
2018, Pediatric Clinics of North America
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As a result, the hypoglycemia often is not as severe as in GSD I, and is typically associated with prominent ketosis. Muscle involvement leads to a chronic myopathy, muscle weakness, and pain, but these manifestations do not present in childhood.47 Although fasting hypoglycemia can occur, most people present after failure to thrive, hepatomegaly, or abnormal hepatic transaminases are incidentally found (see Table 3).
Exercise training in metabolic myopathies
2016, Revue Neurologique
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It therefore comes as no surprise that inborn errors of muscle fat oxidation become symptomatic, not after short burst of exercise like muscle glycogenoses but after more prolonged exercise sessions. It also follows that maximal oxygen uptake (VO2peak) is often normal in disorders of fat metabolism, whereas VO2peak is typically below 50% of normal in patients with muscle glycogenoses, which often compromises performance of everyday tasks [16–20]. In healthy subjects, the main limitation to peak aerobic exercise is oxygen delivery (cardiac output) to the working muscles [21].
Metabolic myopathies encompass muscle glycogenoses (GSD) and disorders of muscle fat oxidation (FAOD). FAODs and GSDs can be divided into two main clinical phenotypes; those with static symptoms related to fixed muscle weakness and atrophy, and those with dynamic, exercise-related symptoms that are brought about by a deficient supply of ATP. Together with mitochondrial myopathies, metabolic myopathies are unique among muscle diseases, as the limitation in exercise performance is not solely caused by structural damage of muscle, but also or exclusively related to energy deficiency. ATP consumption can increase 50–100-fold in contracting, healthy muscle from rest to exercise, and testing patients with exercise is therefore an appropriate approach to disclose limitations in work capacity and endurance in metabolic myopathies. Muscles rely almost exclusively on muscle glycogen in the initial stages of exercise and at high work intensities. Thus, patients with GSDs typically have symptoms early in exercise, have low peak work capacities and develop painful contractures in exercised muscles. Muscle relies on fat oxidation at rest and to a great extent during prolonged exercise, and therefore, patients with FAODs typically develop symptoms later in exercise than patients with GSDs. Due to the exercise-related symptoms in metabolic myopathies, patients generally have been advised to shun physical training. However, immobility is associated with multiple health issues, and may even cause unwanted metabolic adaptations, such as increased dependence on glycogen use and a reduced capacity for fatty acid oxidation, which is detrimental in GSDs. Training has not been studied systematically in any FAODs and in just a few GSDs. However, studies on single bouts of exercise in most metabolic myopathies show that particularly moderate intensity aerobic exercise is well tolerated in these conditions. Even low-intensity resistance training of short duration is tolerated in McArdle disease. Training in patients with FAOD potentially can also expand the metabolic bottleneck by increasing expression of the defective, but partially functional enzyme. Exercise performance in metabolic myopathies can be improved by different fuel supplementations and dietary interventions and should be considered as adjunct therapy to exercise training.
Cross-sectional retrospective study of muscle function in patients with glycogen storage disease type III
2016, Neuromuscular Disorders
Glycogen storage disease type III is an inherited metabolic disorder characterized by liver and muscle impairment. This study aimed to identify promising muscle function measures for future studies on natural disease progression and therapeutic trials. The age-effect on the manual muscle testing (MMT), the hand-held dynamometry (HHD), the motor function measure (MFM) and the Purdue pegboard test was evaluated by regression analysis in a cross-sectional retrospective single site study. In patients aged between 13 and 56 years old, the Purdue pegboard test and dynamometry of key pinch and knee extension strength were age-sensitive with annual losses of 1.49, 1.10 and 0.70% of the predicted values (%pred), respectively. The MFM score and handgrip strength were also age-sensitive but only in patients older than 29 and 37 years old with annual losses of 1.42 and 1.84%pred, respectively. Muscle strength assessed by MMT and elbow extension measured by HHD demonstrated an annual loss of less than 0.50%pred and are thus unlikely to be promising outcome measures for future clinical trials. In conclusion, our results identified age-sensitive outcomes from retrospective data and may serve for future longitudinal studies in which an estimation of the minimal number of subjects is provided.
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In the human body, glycogen is a branched polymer of glucose stored mainly in the liver and the skeletal muscle that supplies glucose to the blood stream during fasting periods and to the muscle cells during muscle contraction. Glycogen has been identified in other tissues such as brain, heart, kidney, adipose tissue, and erythrocytes, but glycogen function in these tissues is mostly unknown. Glycogen synthesis requires a series of reactions that include glucose entrance into the cell through transporters, phosphorylation of glucose to glucose 6-phosphate, isomerization to glucose 1-phosphate, and formation of uridine 5ʹ-diphosphate-glucose, which is the direct glucose donor for glycogen synthesis. Glycogenin catalyzes the formation of a short glucose polymer that is extended by the action of glycogen synthase. Glycogen branching enzyme introduces branch points in the glycogen particle at even intervals. Laforin and malin are proteins involved in glycogen assembly but their specific function remains elusive in humans. Glycogen is accumulated in the liver primarily during the postprandial period and in the skeletal muscle predominantly after exercise. In the cytosol, glycogen breakdown or glycogenolysis is carried out by two enzymes, glycogen phosphorylase which releases glucose 1-phosphate from the linear chains of glycogen, and glycogen debranching enzyme which untangles the branch points. In the lysosomes, glycogen degradation is catalyzed by α-glucosidase. The glucose 6-phosphatase system catalyzes the dephosphorylation of glucose 6-phosphate to glucose, a necessary step for free glucose to leave the cell. Mutations in the genes encoding the enzymes involved in glycogen metabolism cause glycogen storage diseases.

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^☆: Statistical analysis: Statistical analysis was conducted by Nicolai Preisler, MD.

^☆☆: Funding: The study was supported by the AFM [no. 15205], the Association Francophone des Glycogénoses, and the Sara and Ludvig Elssas Foundation.

^★: Disclosure statement: The authors have nothing to disclose pertaining to the present work, however, three authors report disclosures unrelated to the present work: NP, PL and JV report having received research support, honoraria, and travel funding from the Genzyme Corporation. PL and JV are members of the Genzyme Pompe Disease Advisory Board. JV works as a consultant for Lundbeck Pharmaceutical Company.

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Exercise intolerance in Glycogen Storage Disease Type III: Weakness or energy deficiency?☆,☆☆,★

Abstract

Highlights

Introduction

Section snippets

Subjects and methods

Peak exercise capacity

Discussion

Acknowledgments

J. Biol. Chem.

J. Pediatr.

J. Pediatr.

Genet. Med.

J. Neurol. Sci.

Neuromuscul. Disord.

J. Nutr.

Carbohydrate metabolism I: major metabolic pathways and their control

The subgroups of type 3 glycogenosis

Eur. J. Biochem.

Glycogen storage disease type III (glycogen debranching enzyme deficiency): correlation of biochemical defects with myopathy and cardiomyopathy

Ann. Intern. Med.