Type IV Glycogen Storage Disease
- Author: Wayne E Anderson, DO, FAHS, FAAN; Chief Editor: George T Griffing, MD more...
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, which is due to defective glycogen synthase, is also 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 and physical examination, muscle biopsy, electromyelography, ischemic forearm test, and creatine kinase level. Biochemical assay for enzyme activity is the method of definitive diagnosis.
Branching enzyme defect results in an abnormal glycogen structure that is unique to Andersen disease (GSD type IV). Clinically, hepatosplenomegaly, cirrhosis of the liver, and hepatic failure are major concerns.
Transglucosidase, which is found in all tissues, is deficient. The condition is autosomal recessive. Due to abnormal glycogen, hepatic deposition may occur and result in severe cirrhosis, hepatic failure, or neuromuscular failure. It also can present as abnormal liver function tests in its mildest presentation.
Cardiac and skeletal muscle may show PAS+ eosinophilic cytoplasmic inclusions.
Bruno and colleagues, Janecke et al, and others have demonstrated several novel mutations of the branching enzyme gene resulting in GSD IV.[2, 3, 4, 5]
Lamperti et al noted a novel mutation in an infant who died at age 1 month of cardiorespiratory failure. The branching enzyme gene sequence was found to contain a homozygous nonsense mutation, p.E152X, in exon 4, that correlated with a virtual absence of branching enzyme biochemical activity in muscles and fibroblasts, as well as with a complete absence of such activity in the liver and heart.
The infant presented with symptoms consistent with congenital GSD IV, including severe hypotonia, dilatative cardiomyopathy, mild hepatopathy, and brain lateral ventricle hemorrhage. Muscle, heart, and liver specimens contained numerous vacuoles filled with PAS+ diastase-resistant materials, while electron microscopy revealed polyglucosan accumulations in all of the examined tissues. Polyglucosan was also found in vacuolated neurons.
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. GSD IV is very rare.
Serious morbidities include hepatic failure, hepatosplenomegaly, and cardiomyopathy (less frequent).
In general, GSDs present in childhood. Later onset correlates with a less severe form. Liver failure may occur in the first 5 years of life due to deposition of glycogen.
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