History

Early clinical findings include hepatomegaly (98%), hypoglycemia (53%), failure to thrive (49%), and recurrent illness and/or infections (17%).^[13]

Laboratory findings include ketonic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases.^[2]

Myopathy presents as muscle weakness and elevated creatine kinase (CK); it progresses slowly and becomes prominent in the third to fourth decade of life.

Cognitive deficits—impaired working memory, planning skills, the capacity to elaborate and maintain strategies, conceptualization and rule generation, and a generalized slowness—have been described in patients with GSD III.^[14]

Physical Examination

Hepatomegaly is the most common presenting sign in patients with GSD III. Hepatomegaly usually resolves during puberty, and growth accelerates, with the attainment of normal adult height.^[15] In adult patients with GSD III, a decrease in liver progression may be a sign of liver cirrhosis; the median age of cirrhosis diagnosis is 18 years old.^[13]

Cardiac findings vary according to the degree and type of cardiac involvement. The most common cardiac abnormality in patients with GSD III is left ventricular hypertrophy^[1]; findings on physical examination include a sustained, displaced point of maximal impulse.

Differential Diagnoses

Austin SL, Proia AD, Spencer-Manzon MJ, et al. Cardiac Pathology in Glycogen Storage Disease Type III. J Inherit Metab Dis. 2012 January 31. 6:65–72. [QxMD MEDLINE Link]. [Full Text].
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Hoogeveen IJ, van der Ende RM, van Spronsen FJ, et al. Normoglycemic Ketonemia as Biochemical Presentation in Ketotic Glycogen Storage Disease. J Inherit Metab Dis. 2015 November 3. 28:41-47. [QxMD MEDLINE Link]. [Full Text].
Dagli A, Sentner CP, Weinstein DA. Glycogen Storage Disease Type III. GeneReviews® [Internet]. 2016 December 29. [Full Text].
Bao Y, Dawson Jr TL, Chen YT. Human glycogen debranching enzyme gene (AGL): complete structural organization and characterization of the 5' flanking region. Genomics. 1 December 1996. 38:155-165. [QxMD MEDLINE Link]. [Full Text].
Aoyama Y, Ozer I, Demirkol M, et al. Molecular features of 23 patients with glycogen storage disease type III in Turkey: a novel mutation p.R1147G associated with isolated glucosidase deficiency, along with 9 AGL mutations. Journal of Human Genetics. 2009 Oct 17. 54:681-686. [QxMD MEDLINE Link]. [Full Text].
The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff. [Full Text].
Lu C, Qiu Z, Sun M, Wang W, Wei M, Zhang X. Spectrum of AGL mutations in Chinese patients with glycogen storage disease type III: identification of 31 novel mutations. Journal of Human Genetics. 2016 March 17. 61(7):641-645. [QxMD MEDLINE Link]. [Full Text].
Ko JS, Moon JS, Seo JK, Yang HR, Chang JY, Park SS. A mutation analysis of the AGL gene in Korean patients with glycogen storage disease type III. Journal of Human Genetics. 2013 Nov 21. 59(1):42-45. [QxMD MEDLINE Link]. [Full Text].
Mili A, Charfeddine IB, Mamaï O, et al. Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III. Journal of Human Genetics. 2011 November 17. 57(3):170–175. [QxMD MEDLINE Link]. [Full Text].
Parvari R, Moses S, Shen J, Hershkovitz E, Lerner A, Chen YT. A single-base deletion in the 3'-coding region of glycogen-debranching enzyme is prevalent in glycogen storage disease type IIIA in a population of North African Jewish patients. European Journal of Human Genetics. 1997. 5(5):266–270. [QxMD MEDLINE Link]. [Full Text].
Santer R, Kinner M, Steuerwald U. Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands. European Journal of Human Genetics. 2001 June 21. 9(5):388-391. [QxMD MEDLINE Link]. [Full Text].
Sentner CP, Hoogeveen IJ, Weinstein DA, et al. Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome. J Inherit Metab Dis. 2016 April 22. 39(5):697-704. [QxMD MEDLINE Link]. [Full Text].
Michon CC, Gargiulo M, Hahn-Barma V, et al. Cognitive profile of patients with glycogen storage disease type III: a clinical description of seven cases. J Inherit Metab Dis. 2014 November 12. 38(3):573-580. [QxMD MEDLINE Link]. [Full Text].
Coleman RA, Winter HS, Wolf B & Chen YT. Glycogen debranching enzyme deficiency: long-term study of serum enzyme activities and clinical features. J Inherit Metab Dis. 1992 March 30. 15(6):869-881. [QxMD MEDLINE Link]. [Full Text].
Mogahed EA, Girgis MY, Sobhy R, Elhabashy H, Abdelaziz OM, El-Karaksy H. Skeletal and cardiac muscle involvement in children with glycogen storage disease type III. Eur J Pediatr. 2015 Nov. 174 (11):1545-8. [QxMD MEDLINE Link].
Hobson-Webb LD, Austin SL, Bali DS & Kishnani PS. The electrodiagnostic characteristics of Glycogen Storage Disease Type III. Genetics in Medicine. 2010 JulY. 12(7):440-445. [QxMD MEDLINE Link]. [Full Text].
Valayannopoulos V, Bajolle F, Arnoux JB, Dubois S, Sannier N, Baussan C, et al. Successful treatment of severe cardiomyopathy in glycogen storage disease type III With D,L-3-hydroxybutyrate, ketogenic and high-protein diet. Pediatr Res. 2011 Dec. 70(6):638-41. [QxMD MEDLINE Link].
Slonim AE, Weisberg C, Benke P, Evans OB & Burr IM. Reversal of debrancher deficiency myopathy by the use of high-protein nutrition. Annals of neurology. 1982 April. 11(4):420-422. [QxMD MEDLINE Link]. [Full Text].
Dagli AI, Zori RT, McCune H, Ivsic T, Maisenbacher MK & Weinstein DA. Reversal of glycogen storage disease type IIIa-related cardiomyopathy with modification of diet. J Inherit Metab Dis. 2009 Dec. 32:103-106. [QxMD MEDLINE Link]. [Full Text].
Zingone A, Hiraiwa H, Pan CJ, et al. Correction of glycogen storage disease type 1a in a mouse model by gene therapy. J Biol Chem. 2000 Jan 14. 275(2):828-32. [QxMD MEDLINE Link].
Lim JA, Choi SJ, Gao F, Kishnani PS & Sun B. A Novel Gene Therapy Approach for GSD III Using an AAV Vector Encoding a Bacterial Glycogen Debranching Enzyme. Molecular Therapy. Methods & Clinical Development. 2020 Sept. 18:240-249. [Full Text].
Bijvoet AG, Van Hirtum H, Vermey M, et al. Pathological features of glycogen storage disease type II highlighted in the knockout mouse model. J Pathol. 1999 Nov. 189(3):416-24. [QxMD MEDLINE Link].
Matern D, Starzl TE, Arnaout W, et al. Liver transplantation for glycogen storage disease types I, III, and IV. Eur J Pediatr. 1999 Dec. 158 Suppl 2:S43-8. [QxMD MEDLINE Link].
Cheng A, Zhang M, Okubo M, et al. Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions. Hum Mol Genet. 2009 Jun 1. 18(11):2045-52. [QxMD MEDLINE Link]. [Full Text].
Endo Y, Fateen E, El Shabrawy M, et al. Egyptian glycogen storage disease type III - identification of six novel AGL mutations, including a large 1.5 kb deletion and a missense mutation p.L620P with subtype IIId. Clin Chem Lab Med. 2009. 47(10):1233-8. [QxMD MEDLINE Link].
Mili A, Ben Charfeddine I, Mamaï O, Abdelhak S, Adala L, Amara A, et al. Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III. J Hum Genet. 2012 Mar. 57(3):170-5. [QxMD MEDLINE Link].
Lam CW, Lee AT, Lam YY, et al. DNA-based subtyping of glycogen storage disease type III: mutation and haplotype analysis of the AGL gene in Chinese. Mol Genet Metab. 2004 Nov. 83(3):271-5. [QxMD MEDLINE Link].
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Kalkan Ucar S, Coker M, et al. A monocentric pilot study of an antioxidative defense and hsCRP in pediatric patients with glycogen storage disease type IA and III. Nutr Metab Cardiovasc Dis. 2009 Jul. 19(6):383-90. [QxMD MEDLINE Link].
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Valayannopoulos V, Bajolle F, Arnoux JP, et al. Successful treatment of severe cardiomyopathy in glycogen storage disease type III With D,L-3-hydroxybutyrate, ketogenic and high-protein diet. Pediatr Res. 2011 Dec. 70(6):638-641. [Full Text].
Sentner CP, Caliskan K, Vletter KB & Smit GP. Heart Failure Due to Severe Hypertrophic Cardiomyopathy Reversed by Low Calorie, High Protein Dietary Adjustments in a Glycogen Storage Disease Type IIIa Patient. JIMD Rep. 2012. 5:13-16. [QxMD MEDLINE Link]. [Full Text].

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Author

Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT Associate Professor of Medicine, Program Director, Endocrinology, Diabetes and Metabolism Fellowship Program, Director for Diversity in Graduate Medical Education, University of Arizona College of Medicine-Phoenix; Assistant Professor of Medicine, Mayo College of Medicine, Mayo Clinic Arizona; Staff Endocrinologist, Phoenix Veterans Hospital (VAMC)

Ricardo R Correa Marquez, MD, EsD, FACP, FACE, FAPCR, CMQ, ABDA, FACHT is a member of the following medical societies: Academy of Physicians in Clinical Research, American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Healthcare Trustees, American College of Physicians, American Medical Association, American Thyroid Association, Association of Program Directors in Endocrinology, Endocrine Society, National Hispanic Medical Association, World Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Sergio Mellado Flores, MD International Medical Graduate

Sergio Mellado Flores, MD is a member of the following medical societies: American College of Physicians, National Hispanic Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for Physician Leadership, American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society, International Society for Clinical Densitometry, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Wayne E Anderson, DO, FAHS, FAAN Assistant Professor of Internal Medicine/Neurology, College of Osteopathic Medicine of the Pacific Western University of Health Sciences; Clinical Faculty in Family Medicine, Touro University College of Osteopathic Medicine; Clinical Instructor, Departments of Neurology and Pain Management, California Pacific Medical Center

Wayne E Anderson, DO, FAHS, FAAN is a member of the following medical societies: American Academy of Neurology, American Headache Society, California Medical Association, California Neurology Society, International Headache Society, San Francisco Medical Society, San Francisco Neurological Society

Disclosure: Nothing to disclose.

Sections Type III Glycogen Storage Disease (Forbes-Cori Disease)
Overview
Presentation
DDx
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Type III Glycogen Storage Disease (Forbes-Cori Disease) Clinical Presentation

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