Type III Glycogen Storage Disease

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Background

A glycogen storage disease (GSD) results from the absence of enzymes that ultimately convert glycogen compounds to glucose. Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences, but, in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.

The following list contains a quick reference for 8 of the GSD types:

The chart below demonstrates where various forms of GSD affect metabolic carbohydrate pathways.



View Image

Metabolic pathways of carbohydrates.

Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type IIIa, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, Von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity. The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, a GSD type 0 also exists, which is due to defective glycogen synthase.

These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms. In general, GSDs are inherited as autosomal recessive conditions. Several different mutations have been reported for each disorder.

Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations. In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.

Diagnosis depends on patient history and physical examination, muscle biopsy, electromyelography, ischemic forearm test, and creatine kinase levels. Biochemical assay for enzyme activity is the method of definitive diagnosis.

The debranching enzyme converts glycogen to glucose-1,6-phosphate. Deficiency leads to liver disease, with subsequent hypoglycemia and seizure. Progressive muscle weakness also occurs.

Pathophysiology

With an enzyme defect, carbohydrate metabolic pathways are blocked and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect, and each enzyme is in specific, or most, body tissues.

The enzyme amylo-1,6-glucosidase is deficient, leading to an accumulation of dextrin. The site of glycogen accumulation is primarily cytoplasmic. Conversion generally is a one-way reaction from glycogen to glucose-1,6-phosphate. The enzyme is found in all tissues.

Disease results from a pan-deficiency of the enzyme (GSD IIIa) or muscle-specific retention of glycogen debranching enzyme (GSD IIIb). The condition is autosomal recessive. No common mutation has been described in Cori disease (types a and b), although 2 alleles have been reported for GSD IIIb and 1 allele has been found in North African Jewish people with GSD IIIa. The first report of a causative missense mutation was published in 1999 based on the work of Okubo and colleagues.[1, 2, 3, 4]

Although the most prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe Islands, Mili et al used molecular analysis to reveal 3 novel mutations and 5 known mutations among 22 Tunisian patients with GSD III.[5]

GSD type IIIb is caused by mutation in exon 3 of the glycogen debranching enzyme. Lam and colleagues demonstrate different haplotypes for GSD type IIIa.[6] GSD III can occur not only in humans, but also in other mammals.

Epidemiology

Frequency

International

Herling and colleagues studied the incidence and frequency of inherited metabolic conditions in British Columbia. GSDs are found in 2.3 children per 100,000 births per year. In non-Ashkenazi Jewish people of North Africa, the frequency has been reported as 1 out of 5400 people. Zimakas and Rodd report the rare presence of GSD type III in Inuit children.[7]

Mortality/Morbidity

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Kalkan et al conducted a study on 31 patients with GSD Ia or III to determine why patients with these conditions do not tend to develop premature atherosclerosis, even though hyperlipidemia is a feature of both diseases.[10] Marked hypertriglyceridemia was found in the GSD Ia group (22 patients), while hypercholesterolemia with elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol levels was found in the GSD III group (9 patients). The study also included 19 healthy individuals.

The authors found that despite the presence of dyslipidemia in the GSD Ia and III patients, their high sensitivity C-reactive protein levels were the same as in the healthy subjects. The GSD Ia patients had elevated antioxidant activity, although their antioxidant enzyme activity did not differ significantly from that of the healthy subjects. The authors suggested increased antioxidative protection in GSD Ia patients may be associated not only with elevated levels of uric acid (an antioxidant) found in these patients, but also with the use of supplemental vitamin E.

Age

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History

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Physical

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Laboratory Studies

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Imaging Studies

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Other Tests

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Histologic Findings

Muscle biopsy is periodic acid-Schiff positive with basophilic deposits in all tissues, including the CNS.

Medical Care

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Surgical Care

Liver transplantation may be indicated for patients with hepatic malignancy. Whether transplantation prevents further complications is not clear, although a study by Matern and colleagues demonstrated posttransplantation correction of metabolic abnormalities.[15]

Consultations

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Diet

Cornstarch therapy may be beneficial in reducing hypoglycemia.

Complications

See the list below:

Prognosis

See the list below:

Author

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

Disclosure: Nothing to disclose.

Specialty Editors

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.

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

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

Disclosure: Nothing to disclose.

References

  1. Okubo M, Kanda F, Horinishi A, et al. Glycogen storage disease type IIIa: first report of a causative missense mutation (G1448R) of the glycogen debranching enzyme gene found in a homozygous patient. Hum Mutat. 1999 Dec. 14(6):542-3. [View Abstract]
  2. 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. J Hum Genet. 2009 Nov. 54(11):681-6. [View Abstract]
  3. 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. [View Abstract]
  4. 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. [View Abstract]
  5. 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. [View Abstract]
  6. 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. [View Abstract]
  7. Zimakas PJ, Rodd CJ. Glycogen storage disease type III in Inuit children. CMAJ. 2005 Feb 1. 172(3):355-8. [View Abstract]
  8. Ingle SA, Moulick ND, Ranadive NU, Khedekar K. Hepatocellular failure in glycogen storage disorder type 3. J Assoc Physicians India. 2004 Feb. 52:158-60. [View Abstract]
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  14. 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. [View Abstract]
  15. 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. [View Abstract]
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Metabolic pathways of carbohydrates.

Metabolic pathways of carbohydrates.