Type V Glycogen Storage Disease 

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 diagram below illustrates metabolic pathways of carbohydrates.

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)

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, GSD type 0 also is described and is a disorder causing glycogen deficiency 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.^[1]

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 findings from patient history and physical examination, creatine kinase testing, muscle biopsy, electromyelography, and ischemic forearm testing. Biochemical assay for enzyme activity is the method of definitive diagnosis.

Myophosphorylase, the deficient enzyme in McArdle disease, is found in muscle tissue. Myophosphorylase deficiency causes muscle cramps, pain, and stiffness. One hallmark of McArdle disease is weakness with exertion. Proximal muscle weakness may progress with time, and no specific treatment exists.

Recent research

To study the role of fat metabolism in GSD type V, Andersen et al manipulated the availability of free fatty acid for oxidation during exercise in 10 patients with the disease.^[2] The patients, who cycled at a constant workload corresponding to 70% of their maximum oxygen consumption, received either nicotinic acid or 20% Intralipid infusion, which, respectively, reduced or increased free fatty acid availability.

Comparing their trial results with those of placebo and glucose infusion studies, the authors concluded that although during exercise lipids are an important fuel source in persons with GSD type V, maximal fat oxidation rates during exercise cannot be raised above physiologically normal rates in these patients. Andersen et al suggested that this limitation results from glycolytic flux impairment, which causes a "metabolic bottleneck" in the tricarboxylic acid cycle.

The phenotype of the individual with GSD results from an enzyme defect. Carbohydrate metabolic pathways are blocked, leading to excess glycogen accumulation in affected tissues and/or disturbances in energy production. Several gene mutations have been described.^[1]

Fatty acids and glucose serve as substrates for energy production. With intense exercise, glucose from glycogen stores in muscle becomes the predominant resource. Fatigue develops when the glycogen supply is exhausted.^{[3, 4]} Each GSD represents a specific enzyme defect, and each enzyme is in specific, or most, body tissues. Myophosphorylase is found in muscle. Hypoglycemia is not an expected finding because liver phosphorylase is not involved.

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 severe exercise intolerance.

Age

• In general, GSDs present in childhood. Later onset correlates with a less severe form. Consider Pompe disease if onset is in infancy.
• The majority of patients with McArdle disease present in the second to third decade of life.
• Wolfe and colleagues report a unique case of McArdle disease presenting in a person aged 73 years.^[5] Felice and colleagues and Pourmand and colleagues also report late presentations. Physicians should have clinical suspicion regardless of age of presentation.^{[6, 7]}