Current status and progress in the diagnosis and treatment of glycogen storage-related cardiomyopathy_West China Medical Journal

Authors：

ZHAO Jianxun ,  WANG Lin

Department of Cardiology, Chengdu Shang Jin Nan Fu Hospital / Shang Jin Hospital of West China Hospital, Sichuan University, Chengdu, Sichuan 611731, P. R. China;

Corresponding?author：

WANG Lin, Email: wangl108@yeah.net

Keywords：

Glycogen storage; hypertrophic cardiomyopathy; Pompe disease; PRKAG2 cardiac syndrome; Danon disease

DOI：

10.7507/1002-0179.202512091

Video：

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Glycogen storage-related cardiomyopathy refers to a group of rare hereditary disorders caused by genetic defects, characterized by aberrant glycogen accumulation in the myocardium. It includes glycogen storage diseases that can affect the myocardium, PRKAG2 cardiac syndrome, and Danon disease. Cardiac manifestations are predominantly characterized by a hypertrophic cardiomyopathy phenotype. The diagnostic workflow is initiated with cues from distinctive clinical presentations and family history, while genetic testing serves as the core diagnostic modality. Most of these conditions are managed with empirical symptomatic therapies. Currently, adeno-associated virus based gene therapy agents have entered clinical trials, with preliminary findings demonstrating favorable safety and efficacy profiles, thus holding promise as disease-specific therapeutic strategies. This article elaborates on the recent progress in the diagnosis and management of glycogen storage-related cardiomyopathy, along with the challenges confronted in this field, aiming to provide a reference for the clinical practice of such diseases.

Citation： ZHAO Jianxun, WANG Lin. Current status and progress in the diagnosis and treatment of glycogen storage-related cardiomyopathy. West China Medical Journal, 2026, 41(1): 136-141. doi: 10.7507/1002-0179.202512091 Copy

1.	Gümü? E, ?zen H. Glycogen storage diseases: an update. World J Gastroenterol, 2023, 29(25): 3932-3963.
2.	Dornelles AD, Junges APP, Krug B, et al. Efficacy and safety of enzyme replacement therapy with alglucosidase alfa for the treatment of patients with infantile-onset Pompe disease: a systematic review and metanalysis. Front Pediatr, 2024, 12: 1310317.
3.	Reuser AJJ, van der Ploeg AT, Chien YH, et al. GAA variants and phenotypes among 1, 079 patients with Pompe disease: data from the Pompe registry. Hum Mutat, 2019, 40(11): 2146-2164.
4.	Colburn R, Lapidus D. An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion. Front Pediatr, 2023, 11: 1221140.
5.	Cohen JL, Chakraborty P, Fung-Kee-Fung K, et al. In utero enzyme-replacement therapy for infantile-onset Pompe’s disease. N Engl J Med, 2022, 387(23): 2150-2158.
6.	Bharati S, Serratto M, Dubrow I, et al. The conduction system in Pompe's disease. Pediatr Cardiol, 1982, 2(1): 25-32.
7.	van den Hout HM, Hop W, van Diggelen OP, et al. The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the literature. Pediatrics, 2003, 112(2): 332-340.
8.	Boentert M, Florian A, Dr?ger B, et al. Pattern and prognostic value of cardiac involvement in patients with late-onset pompe disease: a comprehensive cardiovascular magnetic resonance approach. J Cardiovasc Magn Reson, 2016, 18(1): 91.
9.	van Kooten HA, Roelen CHA, Brusse E, et al. Cardiovascular disease in non-classic Pompe disease: a systematic review. Neuromuscul Disord, 2021, 31(2): 79-90.
10.	Goeber V, Banz Y, Kaeberich A, et al. Huge aneurysm of the ascending aorta in a patient with adult-type Pompe’s disease: histological findings mimicking fibrillinopathy. Eur J Cardiothorac Surg, 2013, 43(1): 193-195.
11.	Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J, 2023, 44(37): 3503-3626.
12.	Schoser B, Raben N, Varfaj F, et al. Acid α-glucosidase (GAA) activity and glycogen content in muscle biopsy specimens of patients with Pompe disease: a systematic review. Mol Genet Metab Rep, 2024, 39: 101085.
13.	Dimachkie MM, Barohn RJ, Byrne B, et al. Long-term safety and efficacy of avalglucosidase alfa in patients with late-onset Pompe disease. Neurology, 2022, 99(5): e536-e548.
14.	Desai AK, Baloh CH, Sleasman JW, et al. Benefits of prophylactic short-course immune tolerance induction in patients with infantile pompe disease: demonstration of long-term safety and efficacy in an expanded cohort. Front Immunol, 2020, 11: 1727.
15.	Li C, Desai AK, Gupta P, et al. Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction. Genet Med, 2021, 23(5): 845-855.
16.	Koeberl DD, Koch RL, Lim JA, et al. Gene therapy for glycogen storage diseases. J Inherit Metab Dis, 2024, 47(1): 93-118.
17.	Ma X, Zhuang L, Ma W, et al. AAV9-mediated gene therapy for infantile-onset Pompe’s disease. N Engl J Med, 2025, 392(24): 2438-2446.
18.	Pham QH, Bheemsetty VA, Nguyen PA, et al. Long-term functional correction of pompe disease and increased α-glucosidase expression after gene therapy with novel combinations of muscle-targeted transcriptional Cis-regulatory elements. Hum Gene Ther, 2025, 36(21/22): 1423-1440.
19.	Borie-Guichot M, Tran ML, Génisson Y, et al. Pharmacological chaperone therapy for pompe disease. Molecules, 2021, 26(23): 7223.
20.	Schoser B, Kishnani PS, Bratkovic D, et al. 104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a phase III open-label extension study (ATB200-07). J Neurol, 2024, 271(5): 2810-2823.
21.	Ullman JC, Dick RA, Linzner D, et al. First-in-human evaluation of safety, pharmacokinetics and muscle glycogen lowering of a novel glycogen synthase 1 inhibitor for the treatment of Pompe disease. Clin Pharmacol Ther, 2024, 116(6): 1580-1592.
22.	Angelini C. Exercise, nutrition and enzyme replacement therapy are efficacious in adult Pompe patients: report from EPOC consortium. Eur J Transl Myol, 2021, 31(2): 9798.
23.	Bordoli C, Murphy E, Varley I, et al. A systematic review investigating the effectiveness of exercise training in glycogen storage diseases. Ther Adv Rare Dis, 2022, 3: 26330040221076497.
24.	. Evins A, Mayhew J, Cimms T, et al. Glycogen storage disease type III: a mixed-methods study to assess the burden of disease. Ther Adv Endocrinol Metab, 2024, 15: 20420188231224233.
25.	Hijazi G, Paschall A, Young SP, et al. A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III. Mol Genet Metab Rep, 2021, 29: 100821.
26.	Berling é, Laforêt P, Wahbi K, et al. Narrative review of glycogen storage disorder type III with a focus on neuromuscular, cardiac and therapeutic aspects. J Inherit Metab Dis, 2021, 44(3): 521-533.
27.	Pinós T, Cubbon RM, Santalla A, et al. Cardiovascular involvement in glycogen storage diseases. Nat Rev Cardiol, 2026, 23(1): 39-59.
28.	Kiely BT, Koch RL, Flores L, et al. A novel approach to characterize phenotypic variation in GSD IV: reconceptualizing the clinical continuum. Front Genet, 2022, 13: 992406.
29.	Koch RL, Soler-Alfonso C, Kiely BT, et al. Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: a clinical practice resource. Mol Genet Metab, 2023, 138(3): 107525.
30.	Lucia A, Martinuzzi A, Nogales-Gadea G, et al. Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study group. Neuromuscul Disord, 2021, 31(12): 1296-1310.
31.	Hedberg-Oldfors C, Glamuzina E, Ruygrok P, et al. Cardiomyopathy as presenting sign of glycogenin-1 deficiency-report of three cases and review of the literature. J Inherit Metab Dis, 2017, 40(1): 139-149.
32.	Manche?o N, Braza-Bo?ls A, Muelas N, et al. Cardiac phenotype in glycogen storage disease type XV: a rare cardiomyopathy to bear in mind. Rev Esp Cardiol (Engl Ed), 2021, 74(1): 99-101.
33.	程為坡, 宋曉偉, 張必利. PRKAG2 心臟綜合征研究進展. 中華心血管病雜志, 2024, 52(8): 966-972.
34.	Hu D, Hu D, Liu L, et al. Identification, clinical manifestation and structural mechanisms of mutations in AMPK associated cardiac glycogen storage disease. EBioMedicine, 2020, 54: 102723.
35.	Porto AG, Brun F, Severini GM, et al. Clinical spectrum of PRKAG2 syndrome. Circ Arrhythm Electrophysiol, 2016, 9(1): e003121.
36.	Lopez-Sainz A, Dominguez F, Lopes LR, et al. Clinical features and natural history of PRKAG2 variant cardiac glycogenosis. J Am Coll Cardiol, 2020, 76(2): 186-197.
37.	Thevenon J, Laurent G, Ader F, et al. High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations. Europace, 2017, 19(4): 651-659.
38.	Xu J, Li Z, Liu Y, et al. Danon disease: a case report and literature review. Diagn Pathol, 2021, 16(1): 39.
39.	Wang Y, Jia M, Guo Y, et al. Case report: Danon disease: six family members and literature review. Front Cardiovasc Med, 2022, 9: 842282.
40.	Hong KN, Eshraghian EA, Arad M, et al. International consensus on differential diagnosis and management of patients With Danon disease: JACC state-of-the-art review. J Am Coll Cardiol, 2023, 82(16): 1628-1647.
41.	Brambatti M, Caspi O, Maolo A, et al. Danon disease: gender differences in presentation and outcomes. Int J Cardiol, 2019, 286: 92-98.
42.	Hong KN, Eshraghian E, Khedro T, et al. An international longitudinal natural history study of patients with Danon disease: unique cardiac trajectories identified based on sex and heart failure outcomes. J Am Heart Assoc, 2025, 14(7): e038394.
43.	Greenberg B, Taylor M, Adler E, et al. Phase 1 study of AAV9. LAMP2B gene therapy in danon disease. N Engl J Med, 2025, 392(10): 972-983.
44.	Fan Z, Wan LX, Jiang W, et al. Targeting autophagy with small-molecule activators for potential therapeutic purposes. Eur J Med Chem, 2023, 260: 115722.
45.	Hong KN, Battikha C, John S, et al. Cardiac transplantation in Danon disease. J Card Fail, 2022, 28(4): 664-669.
46.	國家心血管病中心心肌病專科聯盟, 中國醫療保健國際交流促進會心血管精準醫學分會. 中國心肌病綜合管理指南 2025. 中國循環雜志, 2025, 40(5): 420-462.
47.	楊彧潔, 齊樂原, 曹焱柏, 等. 數智化技術在罕見病診療中的應用現狀與展望. 藥物流行病學雜志, 2025, 34(8): 972-985.
48.	郭健, 古麗旦娜·阿斯哈爾, 張抒揚. 罕見病臨床研究數據采集與管理難點和數智化應對策略. 藥物流行病學雜志, 2025, 34(8): 897-907.
49.	東振彩, 劉薇. 天津市兒童醫院 2015—2024 年罕見病患者疾病譜分析. 醫學新知, 2025, 35(8): 903-909.

1. Gümü? E, ?zen H. Glycogen storage diseases: an update. World J Gastroenterol, 2023, 29(25): 3932-3963.
2. Dornelles AD, Junges APP, Krug B, et al. Efficacy and safety of enzyme replacement therapy with alglucosidase alfa for the treatment of patients with infantile-onset Pompe disease: a systematic review and metanalysis. Front Pediatr, 2024, 12: 1310317.
3. Reuser AJJ, van der Ploeg AT, Chien YH, et al. GAA variants and phenotypes among 1, 079 patients with Pompe disease: data from the Pompe registry. Hum Mutat, 2019, 40(11): 2146-2164.
4. Colburn R, Lapidus D. An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion. Front Pediatr, 2023, 11: 1221140.
5. Cohen JL, Chakraborty P, Fung-Kee-Fung K, et al. In utero enzyme-replacement therapy for infantile-onset Pompe’s disease. N Engl J Med, 2022, 387(23): 2150-2158.
6. Bharati S, Serratto M, Dubrow I, et al. The conduction system in Pompe's disease. Pediatr Cardiol, 1982, 2(1): 25-32.
7. van den Hout HM, Hop W, van Diggelen OP, et al. The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the literature. Pediatrics, 2003, 112(2): 332-340.
8. Boentert M, Florian A, Dr?ger B, et al. Pattern and prognostic value of cardiac involvement in patients with late-onset pompe disease: a comprehensive cardiovascular magnetic resonance approach. J Cardiovasc Magn Reson, 2016, 18(1): 91.
9. van Kooten HA, Roelen CHA, Brusse E, et al. Cardiovascular disease in non-classic Pompe disease: a systematic review. Neuromuscul Disord, 2021, 31(2): 79-90.
10. Goeber V, Banz Y, Kaeberich A, et al. Huge aneurysm of the ascending aorta in a patient with adult-type Pompe’s disease: histological findings mimicking fibrillinopathy. Eur J Cardiothorac Surg, 2013, 43(1): 193-195.
11. Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J, 2023, 44(37): 3503-3626.
12. Schoser B, Raben N, Varfaj F, et al. Acid α-glucosidase (GAA) activity and glycogen content in muscle biopsy specimens of patients with Pompe disease: a systematic review. Mol Genet Metab Rep, 2024, 39: 101085.
13. Dimachkie MM, Barohn RJ, Byrne B, et al. Long-term safety and efficacy of avalglucosidase alfa in patients with late-onset Pompe disease. Neurology, 2022, 99(5): e536-e548.
14. Desai AK, Baloh CH, Sleasman JW, et al. Benefits of prophylactic short-course immune tolerance induction in patients with infantile pompe disease: demonstration of long-term safety and efficacy in an expanded cohort. Front Immunol, 2020, 11: 1727.
15. Li C, Desai AK, Gupta P, et al. Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction. Genet Med, 2021, 23(5): 845-855.
16. Koeberl DD, Koch RL, Lim JA, et al. Gene therapy for glycogen storage diseases. J Inherit Metab Dis, 2024, 47(1): 93-118.
17. Ma X, Zhuang L, Ma W, et al. AAV9-mediated gene therapy for infantile-onset Pompe’s disease. N Engl J Med, 2025, 392(24): 2438-2446.
18. Pham QH, Bheemsetty VA, Nguyen PA, et al. Long-term functional correction of pompe disease and increased α-glucosidase expression after gene therapy with novel combinations of muscle-targeted transcriptional Cis-regulatory elements. Hum Gene Ther, 2025, 36(21/22): 1423-1440.
19. Borie-Guichot M, Tran ML, Génisson Y, et al. Pharmacological chaperone therapy for pompe disease. Molecules, 2021, 26(23): 7223.
20. Schoser B, Kishnani PS, Bratkovic D, et al. 104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a phase III open-label extension study (ATB200-07). J Neurol, 2024, 271(5): 2810-2823.
21. Ullman JC, Dick RA, Linzner D, et al. First-in-human evaluation of safety, pharmacokinetics and muscle glycogen lowering of a novel glycogen synthase 1 inhibitor for the treatment of Pompe disease. Clin Pharmacol Ther, 2024, 116(6): 1580-1592.
22. Angelini C. Exercise, nutrition and enzyme replacement therapy are efficacious in adult Pompe patients: report from EPOC consortium. Eur J Transl Myol, 2021, 31(2): 9798.
23. Bordoli C, Murphy E, Varley I, et al. A systematic review investigating the effectiveness of exercise training in glycogen storage diseases. Ther Adv Rare Dis, 2022, 3: 26330040221076497.
24. . Evins A, Mayhew J, Cimms T, et al. Glycogen storage disease type III: a mixed-methods study to assess the burden of disease. Ther Adv Endocrinol Metab, 2024, 15: 20420188231224233.
25. Hijazi G, Paschall A, Young SP, et al. A retrospective longitudinal study and comprehensive review of adult patients with glycogen storage disease type III. Mol Genet Metab Rep, 2021, 29: 100821.
26. Berling é, Laforêt P, Wahbi K, et al. Narrative review of glycogen storage disorder type III with a focus on neuromuscular, cardiac and therapeutic aspects. J Inherit Metab Dis, 2021, 44(3): 521-533.
27. Pinós T, Cubbon RM, Santalla A, et al. Cardiovascular involvement in glycogen storage diseases. Nat Rev Cardiol, 2026, 23(1): 39-59.
28. Kiely BT, Koch RL, Flores L, et al. A novel approach to characterize phenotypic variation in GSD IV: reconceptualizing the clinical continuum. Front Genet, 2022, 13: 992406.
29. Koch RL, Soler-Alfonso C, Kiely BT, et al. Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: a clinical practice resource. Mol Genet Metab, 2023, 138(3): 107525.
30. Lucia A, Martinuzzi A, Nogales-Gadea G, et al. Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study group. Neuromuscul Disord, 2021, 31(12): 1296-1310.
31. Hedberg-Oldfors C, Glamuzina E, Ruygrok P, et al. Cardiomyopathy as presenting sign of glycogenin-1 deficiency-report of three cases and review of the literature. J Inherit Metab Dis, 2017, 40(1): 139-149.
32. Manche?o N, Braza-Bo?ls A, Muelas N, et al. Cardiac phenotype in glycogen storage disease type XV: a rare cardiomyopathy to bear in mind. Rev Esp Cardiol (Engl Ed), 2021, 74(1): 99-101.
33. 程為坡, 宋曉偉, 張必利. PRKAG2 心臟綜合征研究進展. 中華心血管病雜志, 2024, 52(8): 966-972.
34. Hu D, Hu D, Liu L, et al. Identification, clinical manifestation and structural mechanisms of mutations in AMPK associated cardiac glycogen storage disease. EBioMedicine, 2020, 54: 102723.
35. Porto AG, Brun F, Severini GM, et al. Clinical spectrum of PRKAG2 syndrome. Circ Arrhythm Electrophysiol, 2016, 9(1): e003121.
36. Lopez-Sainz A, Dominguez F, Lopes LR, et al. Clinical features and natural history of PRKAG2 variant cardiac glycogenosis. J Am Coll Cardiol, 2020, 76(2): 186-197.
37. Thevenon J, Laurent G, Ader F, et al. High prevalence of arrhythmic and myocardial complications in patients with cardiac glycogenosis due to PRKAG2 mutations. Europace, 2017, 19(4): 651-659.
38. Xu J, Li Z, Liu Y, et al. Danon disease: a case report and literature review. Diagn Pathol, 2021, 16(1): 39.
39. Wang Y, Jia M, Guo Y, et al. Case report: Danon disease: six family members and literature review. Front Cardiovasc Med, 2022, 9: 842282.
40. Hong KN, Eshraghian EA, Arad M, et al. International consensus on differential diagnosis and management of patients With Danon disease: JACC state-of-the-art review. J Am Coll Cardiol, 2023, 82(16): 1628-1647.
41. Brambatti M, Caspi O, Maolo A, et al. Danon disease: gender differences in presentation and outcomes. Int J Cardiol, 2019, 286: 92-98.
42. Hong KN, Eshraghian E, Khedro T, et al. An international longitudinal natural history study of patients with Danon disease: unique cardiac trajectories identified based on sex and heart failure outcomes. J Am Heart Assoc, 2025, 14(7): e038394.
43. Greenberg B, Taylor M, Adler E, et al. Phase 1 study of AAV9. LAMP2B gene therapy in danon disease. N Engl J Med, 2025, 392(10): 972-983.
44. Fan Z, Wan LX, Jiang W, et al. Targeting autophagy with small-molecule activators for potential therapeutic purposes. Eur J Med Chem, 2023, 260: 115722.
45. Hong KN, Battikha C, John S, et al. Cardiac transplantation in Danon disease. J Card Fail, 2022, 28(4): 664-669.
46. 國家心血管病中心心肌病專科聯盟, 中國醫療保健國際交流促進會心血管精準醫學分會. 中國心肌病綜合管理指南 2025. 中國循環雜志, 2025, 40(5): 420-462.
47. 楊彧潔, 齊樂原, 曹焱柏, 等. 數智化技術在罕見病診療中的應用現狀與展望. 藥物流行病學雜志, 2025, 34(8): 972-985.
48. 郭健, 古麗旦娜·阿斯哈爾, 張抒揚. 罕見病臨床研究數據采集與管理難點和數智化應對策略. 藥物流行病學雜志, 2025, 34(8): 897-907.
49. 東振彩, 劉薇. 天津市兒童醫院 2015—2024 年罕見病患者疾病譜分析. 醫學新知, 2025, 35(8): 903-909.

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