Type Ia Glycogen Storage Disease

Updated: Mar 07, 2017
  • Author: Wayne E Anderson, DO, FAHS, FAAN; Chief Editor: George T Griffing, MD  more...
  • Print
Overview

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. [1]

The diagram below illustrates metabolic pathways of carbohydrates.

Metabolic pathways of carbohydrates 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 [G-6-P] 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, GSD type 0, which is due to defective glycogen synthase, also is recognized.

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

G-6-P deficiency is the specific enzyme deficiency in von Gierke disease. GSD type Ib is a similar condition with the defect in the G-6-P transporter protein. A newly described form, GSD type Ic, does not appear to be related to mutations within the transporter protein.

Next:

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. As noted above, G-6-P, which is found in the liver and kidney, is the specific enzyme that is deficient in von Gierke disease. Glucose-6-phosphate is an intermediate in the glycogen pathway.

Von Gierke disease is an autosomal-recessive condition. Von Gierke disease may be explained by mutations of the phosphohydrolase catalytic unit gene of the G-6-P complex, unlike GSD type Ib and GSD type Ic.

Deficiency of G-6-P blocks the final steps of glycogenolysis and gluconeogenesis. [2] This results in severe hypoglycemia. Glucose production increases with age, making hypoglycemia less of an issue.

Because glucose cannot leave the hepatocyte phosphorylated, an increase in glycolytic pathway metabolites occurs. These intermediates are metabolized into lactate. Lactate may provide the brain with a ready-to-use energy source. By competing with uric acid, lactate decreases renal clearance, resulting in hyperuricemia. Glucose also is shunted into making more triglycerides, causing an increase in low-density and very low-density lipoproteins. [3]

Previous
Next:

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

Immediate morbidity arises from hypoglycemic seizures. Serious long-term complications resulting in morbidity and mortality include nephropathy and hepatic adenoma. [4]

Sex

GSDs are autosomal-recessive conditions, with an equal number of males and females being affected.

Age

In general, GSDs present in childhood. Later onset correlates with a less severe form.

Previous