Background
A glycogen storage disease (GSD) is the result of an enzyme defect. These enzymes normally catalyze reactions 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 image below illustrates the metabolic pathways for carbohydrates.
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 III, 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, there also is a GSD type 0, 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.[1] In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.
Diagnosis depends on muscle biopsy, electromyelography, ischemic forearm test, creatine kinase levels, patient history, and physical examination. Biochemical assay for enzyme activity is the method of definitive diagnosis.
Acid maltase catalyzes the hydrogenation reaction of maltose to glucose. Acid maltase deficiency is a unique glycogenosis since glycogen accumulation is lysosomal rather than in the cytoplasm. It also has a unique clinical presentation depending on age at onset, ranging from fatal hypotonia and cardiomegaly in the neonate to muscular dystrophy in adults.
Glucose-6-phosphatase (G-6-P) is the specific enzyme deficiency in Von Gierke disease. GSD type 1b is a similar condition with a defective G-6-P transporter protein.[2, 3] A newly described form, GSD type 1c, is not thought to be related to a transporter protein mutation.
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 G-6-P transporter protein is found in the liver and kidney.
GSD type Ib is an autosomal recessive condition.
Glucose-6-phosphate is an intermediate in glycogen synthesis and glucose metabolism. GSD type Ib differs from GSD type Ia in that it is not explained by mutations of the phosphohydrolase gene. Veiga-da-Cuhna and colleagues provide evidence that all non-1a cases can be explained by mutations of the glucose-6-phosphate translocase gene.[4]
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.
Mortality/Morbidity
See the list below:
GSD Ib, unlike GSD Ia, involves bacterial infections including brain abscesses. However, D'Eufemia and colleagues report one case of a 10-year-old boy with GSD II with neutropenia and neutrophil dysfunction but without severe recurrent infections.[5]
Immediate morbidity arises from hypoglycemic seizures.
Serious long-term complications include nephropathy and hepatic adenoma.
Age
See the list below:
Procedures
Given the association of inflammatory bowel disease, endoscopic procedures may be necessary.
Histologic Findings
Liver histology is characterized by hepatocytes distended by glycogen and fat. Associated fibrosis is minimal.
Surgical Care
Liver transplantation may be indicated for patients with hepatic malignancy. It is not clear if transplantation prevents further complications, although a study by Matern and colleagues demonstrated post-transplantation correction of metabolic abnormalities.[10]
Consultations
Gastroenterology consult may be necessary to evaluate the presence or absence of inflammatory bowel disease.
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.
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