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:
0 - Glycogen synthase deficiency
Ia -Glucose-6-phosphatase deficiency (von Gierke disease)
II -Acid maltase deficiency (Pompe disease)
III - Debranching enzyme deficiency (Forbes-Cori disease)
IV - Transglucosidase deficiency (Andersen disease, amylopectinosis)
V - Myophosphorylase deficiency (McArdle disease)
VI - Phosphorylase deficiency (Hers disease)
VII - Phosphofructokinase deficiency (Tarui disease)
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
See the list below:
Immediate morbidity may arise from hypoglycemic seizures that occur in the first decade of life.
Long-term morbidity arises from hepatic disease and progressive muscle weakness.
Ingle and colleagues report sudden mortality by exsanguination related to hepatocellular failure.[8]
Demo and colleagues report two cases of hepatocellular carcinoma as a long-term complication of GSD III, possibly emerging because of increased overall survival with GSD III.[9]
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
See the list below:
In general, GSDs present in childhood.
Later onset correlates with a less severe form.
Consider Pompe disease if onset is in infancy.
Histologic Findings
Muscle biopsy is periodic acid-Schiff positive with basophilic deposits in all tissues, including the CNS.
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]
Diet
Cornstarch therapy may be beneficial in reducing hypoglycemia.
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.
){kind=link}