EDITORIAL
Published Ahead of Print on April 1, 2015 as 10.1212/WNL.0000000000001532
Glycogen storage disease type III The phenotype branches out
Ronald G. Haller, MD
Correspondence to Dr. Haller: Ronald.Haller@ UTSouthwestern.edu Neurology® 2015;84:1–2
Glycogen is a highly branched glucose polymer consisting of chains of a(1-.4) glycosyl bonds with a(1-.6) glycosyl branch points. Glycogen is stored primarily in skeletal muscle and liver as a critical source of energy—in skeletal muscle as a fuel for muscle contraction, in liver as a source of glucose for extrahepatic metabolism. In both tissues, glycogen metabolism is achieved by the coordinated action of glycogen phosphorylase and debrancher. Glycogen phosphorylase splits a(1-4) glycosyl bonds to within 4 residues of a branch point. Glycogen debrancher (amylo-1,6-glucosidase,4-a-glucanotransferase [AGL]) has dual catalytic functions. First it transfers 3 of the final 4 residues at branch points to attach them in an a(1-4) linkage for metabolism by glycogen phosphorylase; then debrancher splits the a(1-6) bond to release the final glycosyl residue as free glucose. A single gene encodes debrancher, and pathogenic mutations usually cause enzyme deficiency in both liver and skeletal muscle (glycogen storage disease type IIIa [GSDIIIa]) with variable involvement of other tissues including heart.1 Glycogen storage disease type V (GSDV) (McArdle disease), due to mutations in PYGM, encoding myophosphorylase, causes selective skeletal muscle deficiency. Despite these genetic differences, GSDIIIa and GSDV might be expected to cause similar muscle symptoms attributable to a restricted ability to break down glycogen to power muscle contractions. Remarkably, debrancher deficiency heretofore has been recognized to cause primarily static symptoms consisting of varying severity and distribution of fixed weakness in contrast to the dynamic (i.e., exercise-induced) symptoms that are characteristic of McArdle disease.1 The study by Preisler et al.2 uses the revealing experiment of exercise to demonstrate that GSDIIIa both dramatically alters muscle metabolism and causes premature exertional fatigue. The fact that GSDIII restricts lactate production with forearm exercise is well-known,3 but the Preisler et al. study shows additional effects upon fuel mobilization and utilization. During maximal cycle
exercise, carbohydrate oxidation is blunted. The average peak respiratory exchange ratio was 0.82, indicating that carbohydrate combustion accounts for only 40% of O2 utilization (VO2). In healthy humans, in contrast, carbohydrate accounts for virtually 100% of VO2 with maximal exercise.4 It seems likely that this restriction in carbohydrate availability contributes to reduced oxidative capacity in these patients.2,5 Limited carbohydrate oxidation is associated with increased dependence upon fat. During peak exercise, 60% of VO2 is attributable to fat oxidation, in contrast to the virtually complete suppression of fat oxidation during peak exercise in healthy subjects.6 During submaximal exercise, fat mobilization and oxidation are high and carbohydrate oxidation is nil.2 Also, the normal increase in hepatic glucose production is blunted and falls progressively along with declining blood glucose as exercise continues.2 A fructose supplement corrects many of these metabolic anomalies, increasing blood glucose levels, muscle lactate production, and carbohydrate oxidation. The authors note similarities between exercise metabolism in debrancher deficiency and in McArdle patients in whom exercise also is associated with a low capacity for carbohydrate oxidation and exaggerated fat mobilization and oxidation.7 However, the character of exercise limitation and premature fatigue in GSDIIIa as revealed in this study differs markedly from McArdle disease. Patients with debrancher deficiency rarely if ever have the signature symptoms of exertional muscle cramps (contractures), rhabdomyolysis, and myoglobinuria that accompany maximal effort muscle contractions in McArdle disease, phosphofructokinase deficiency, and distal glycolytic defects.1 The key manifestation of exercise intolerance in GSDIIIa patients is high and rapidly increasing levels of perceived exertion and premature fatigue during sustained, submaximal exercise. Only one of the patients was able to exercise for 60 minutes. The other patients experienced exhaustion before 30 minutes.2 In our experience, patients with McArdle disease, despite a complete block in glycogen breakdown, are able to exercise for 60 minutes
See page XXX From the Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center; the North Texas VA Medical Center; and the Neuromuscular Center, Institute for Exercise and Environmental Medicine, Dallas, TX. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the editorial. © 2015 American Academy of Neurology
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
without stopping, at heart rates that are equal to or higher than that recorded in the debrancher patients. This result implies that, despite metabolic similarities, the mechanism of fatigue in these 2 conditions is different. The authors advance the logical suggestion that protection from exercise-induced muscle contractures and myoglobinuria in GSDIIIa may be conferred by glycogen chains that remain accessible to metabolism by myophosphorylase. The glycogen that is stored in GSDIII is phosphorylase-limit-dextrin, containing a preponderance of branches and relatively short a(1-4) glycosyl chains.3 This suggests that the severity of the block in glycogen breakdown will increase as glycosyl chains shrink to branch points. In seminal studies by Bergstrom et al.,8 glycogen depletion during sustained submaximal exercise in healthy humans resulted in exhaustion, and the duration of such exercise was shorter with low and greater with high initial levels of glycogen. It seems plausible that fatigue in debrancher deficiency has a similar mechanism of depletion of available glycogen. Oral fructose improved exercise intolerance in the debrancher patients as indicated by an ability to continue submaximal exercise longer and at a higher workload (2 patients) and at a lower level of perceived exertion (all patients).2 This presumably relates to the ability of blood glucose to bypass the metabolic block in skeletal muscle and compensate for impaired hepatic glucose production and low blood glucose. Similarly, IV glucose and oral sucrose substantially improve exercise capacity in McArdle disease.9 The muscle phenotype of GSDIIIa is complex and heterogeneous, likely attributable in part to different mutations with variable effects on glucosidase and transferase function in muscle and other tissues.10 This article shows that fatigability is an important, if neglected, aspect of the phenotype and that the
2
Neurology 84
presence and severity of exercise intolerance varies among patients. Accordingly, further studies are needed to clarify the range of exercise limitations and to better understand the cellular basis of these dynamic symptoms. STUDY FUNDING No targeted funding reported.
DISCLOSURE The author reports no disclosures. Go to Neurology.org for full disclosures.
REFERENCES 1. Kishnani PS, Austin SL, Arn P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med 2010;12:446–463. 2. Preisler N, Laforêt P, Madsen KL, et al. Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III. Neurology 2015;84:xxx–xxx. 3. DiMauro S, Hartwig GB, Hays A, et al. Debrancher deficiency: neuromuscular disorder in 5 adults. Ann Neurol 1979;5:422–436. 4. Jensen TE, Richter EA. Regulation of glucose and glycogen metabolism during and after exercise. J Physiol 2012; 590:1069–1076. 5. Preisler N, Pradel A, Husu E, et al. Exercise intolerance in glycogen storage disease type III: weakness or energy deficiency? Mol Genet Metab 2013;109:14–20. 6. Jeppesen J, Kiens B. Regulation and limitations to fatty acid oxidation during exercise. J Physiol 2012;590:1059–1068. 7. Orngreen MC, Jeppesen TD, Andersen ST, et al. Fat metabolism during exercise in patients with McArdle disease. Neurology 2009;72:718–724. 8. Bergstrom J, Hermansen L, Hultman E, Saltin B. Diet, muscle glycogen and physical performance. Acta Physiol Scand 1967;71:140–150. 9. Vissing J, Haller RG. The effect of oral sucrose on exercise tolerance in patients with McArdle’s disease. N Engl J Med 2003;349:2503–2509. 10. Shen JJ, Chen YT. Molecular characterization of glycogen storage disease type III. Curr Mol Med 2002;2:167–175.
April 28, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Glycogen storage disease type III: The phenotype branches out Ronald G. Haller Neurology published online April 1, 2015 DOI 10.1212/WNL.0000000000001532 This information is current as of April 1, 2015 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2015/04/01/WNL.0000000000 001532.full.html
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Neuromuscular Disease http://www.neurology.org//cgi/collection/all_neuromuscular_disease Glycogenoses http://www.neurology.org//cgi/collection/glycogenoses Hypoglycemia http://www.neurology.org//cgi/collection/hypoglycemia Muscle disease http://www.neurology.org//cgi/collection/muscle_disease
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Published Ahead of Print on April 1, 2015 as 10.1212/WNL.0000000000001532
Glycogen storage disease type III The phenotype branches out
Ronald G. Haller, MD
Correspondence to Dr. Haller: Ronald.Haller@ UTSouthwestern.edu Neurology® 2015;84:1–2
Glycogen is a highly branched glucose polymer consisting of chains of a(1-.4) glycosyl bonds with a(1-.6) glycosyl branch points. Glycogen is stored primarily in skeletal muscle and liver as a critical source of energy—in skeletal muscle as a fuel for muscle contraction, in liver as a source of glucose for extrahepatic metabolism. In both tissues, glycogen metabolism is achieved by the coordinated action of glycogen phosphorylase and debrancher. Glycogen phosphorylase splits a(1-4) glycosyl bonds to within 4 residues of a branch point. Glycogen debrancher (amylo-1,6-glucosidase,4-a-glucanotransferase [AGL]) has dual catalytic functions. First it transfers 3 of the final 4 residues at branch points to attach them in an a(1-4) linkage for metabolism by glycogen phosphorylase; then debrancher splits the a(1-6) bond to release the final glycosyl residue as free glucose. A single gene encodes debrancher, and pathogenic mutations usually cause enzyme deficiency in both liver and skeletal muscle (glycogen storage disease type IIIa [GSDIIIa]) with variable involvement of other tissues including heart.1 Glycogen storage disease type V (GSDV) (McArdle disease), due to mutations in PYGM, encoding myophosphorylase, causes selective skeletal muscle deficiency. Despite these genetic differences, GSDIIIa and GSDV might be expected to cause similar muscle symptoms attributable to a restricted ability to break down glycogen to power muscle contractions. Remarkably, debrancher deficiency heretofore has been recognized to cause primarily static symptoms consisting of varying severity and distribution of fixed weakness in contrast to the dynamic (i.e., exercise-induced) symptoms that are characteristic of McArdle disease.1 The study by Preisler et al.2 uses the revealing experiment of exercise to demonstrate that GSDIIIa both dramatically alters muscle metabolism and causes premature exertional fatigue. The fact that GSDIII restricts lactate production with forearm exercise is well-known,3 but the Preisler et al. study shows additional effects upon fuel mobilization and utilization. During maximal cycle
exercise, carbohydrate oxidation is blunted. The average peak respiratory exchange ratio was 0.82, indicating that carbohydrate combustion accounts for only 40% of O2 utilization (VO2). In healthy humans, in contrast, carbohydrate accounts for virtually 100% of VO2 with maximal exercise.4 It seems likely that this restriction in carbohydrate availability contributes to reduced oxidative capacity in these patients.2,5 Limited carbohydrate oxidation is associated with increased dependence upon fat. During peak exercise, 60% of VO2 is attributable to fat oxidation, in contrast to the virtually complete suppression of fat oxidation during peak exercise in healthy subjects.6 During submaximal exercise, fat mobilization and oxidation are high and carbohydrate oxidation is nil.2 Also, the normal increase in hepatic glucose production is blunted and falls progressively along with declining blood glucose as exercise continues.2 A fructose supplement corrects many of these metabolic anomalies, increasing blood glucose levels, muscle lactate production, and carbohydrate oxidation. The authors note similarities between exercise metabolism in debrancher deficiency and in McArdle patients in whom exercise also is associated with a low capacity for carbohydrate oxidation and exaggerated fat mobilization and oxidation.7 However, the character of exercise limitation and premature fatigue in GSDIIIa as revealed in this study differs markedly from McArdle disease. Patients with debrancher deficiency rarely if ever have the signature symptoms of exertional muscle cramps (contractures), rhabdomyolysis, and myoglobinuria that accompany maximal effort muscle contractions in McArdle disease, phosphofructokinase deficiency, and distal glycolytic defects.1 The key manifestation of exercise intolerance in GSDIIIa patients is high and rapidly increasing levels of perceived exertion and premature fatigue during sustained, submaximal exercise. Only one of the patients was able to exercise for 60 minutes. The other patients experienced exhaustion before 30 minutes.2 In our experience, patients with McArdle disease, despite a complete block in glycogen breakdown, are able to exercise for 60 minutes
See page XXX From the Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center; the North Texas VA Medical Center; and the Neuromuscular Center, Institute for Exercise and Environmental Medicine, Dallas, TX. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the editorial. © 2015 American Academy of Neurology
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
without stopping, at heart rates that are equal to or higher than that recorded in the debrancher patients. This result implies that, despite metabolic similarities, the mechanism of fatigue in these 2 conditions is different. The authors advance the logical suggestion that protection from exercise-induced muscle contractures and myoglobinuria in GSDIIIa may be conferred by glycogen chains that remain accessible to metabolism by myophosphorylase. The glycogen that is stored in GSDIII is phosphorylase-limit-dextrin, containing a preponderance of branches and relatively short a(1-4) glycosyl chains.3 This suggests that the severity of the block in glycogen breakdown will increase as glycosyl chains shrink to branch points. In seminal studies by Bergstrom et al.,8 glycogen depletion during sustained submaximal exercise in healthy humans resulted in exhaustion, and the duration of such exercise was shorter with low and greater with high initial levels of glycogen. It seems plausible that fatigue in debrancher deficiency has a similar mechanism of depletion of available glycogen. Oral fructose improved exercise intolerance in the debrancher patients as indicated by an ability to continue submaximal exercise longer and at a higher workload (2 patients) and at a lower level of perceived exertion (all patients).2 This presumably relates to the ability of blood glucose to bypass the metabolic block in skeletal muscle and compensate for impaired hepatic glucose production and low blood glucose. Similarly, IV glucose and oral sucrose substantially improve exercise capacity in McArdle disease.9 The muscle phenotype of GSDIIIa is complex and heterogeneous, likely attributable in part to different mutations with variable effects on glucosidase and transferase function in muscle and other tissues.10 This article shows that fatigability is an important, if neglected, aspect of the phenotype and that the
2
Neurology 84
presence and severity of exercise intolerance varies among patients. Accordingly, further studies are needed to clarify the range of exercise limitations and to better understand the cellular basis of these dynamic symptoms. STUDY FUNDING No targeted funding reported.
DISCLOSURE The author reports no disclosures. Go to Neurology.org for full disclosures.
REFERENCES 1. Kishnani PS, Austin SL, Arn P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med 2010;12:446–463. 2. Preisler N, Laforêt P, Madsen KL, et al. Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III. Neurology 2015;84:xxx–xxx. 3. DiMauro S, Hartwig GB, Hays A, et al. Debrancher deficiency: neuromuscular disorder in 5 adults. Ann Neurol 1979;5:422–436. 4. Jensen TE, Richter EA. Regulation of glucose and glycogen metabolism during and after exercise. J Physiol 2012; 590:1069–1076. 5. Preisler N, Pradel A, Husu E, et al. Exercise intolerance in glycogen storage disease type III: weakness or energy deficiency? Mol Genet Metab 2013;109:14–20. 6. Jeppesen J, Kiens B. Regulation and limitations to fatty acid oxidation during exercise. J Physiol 2012;590:1059–1068. 7. Orngreen MC, Jeppesen TD, Andersen ST, et al. Fat metabolism during exercise in patients with McArdle disease. Neurology 2009;72:718–724. 8. Bergstrom J, Hermansen L, Hultman E, Saltin B. Diet, muscle glycogen and physical performance. Acta Physiol Scand 1967;71:140–150. 9. Vissing J, Haller RG. The effect of oral sucrose on exercise tolerance in patients with McArdle’s disease. N Engl J Med 2003;349:2503–2509. 10. Shen JJ, Chen YT. Molecular characterization of glycogen storage disease type III. Curr Mol Med 2002;2:167–175.
April 28, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Glycogen storage disease type III: The phenotype branches out Ronald G. Haller Neurology published online April 1, 2015 DOI 10.1212/WNL.0000000000001532 This information is current as of April 1, 2015 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2015/04/01/WNL.0000000000 001532.full.html
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Neuromuscular Disease http://www.neurology.org//cgi/collection/all_neuromuscular_disease Glycogenoses http://www.neurology.org//cgi/collection/glycogenoses Hypoglycemia http://www.neurology.org//cgi/collection/hypoglycemia Muscle disease http://www.neurology.org//cgi/collection/muscle_disease
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2015 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
