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.
* All forms of GSD IV result from defects in the gene that encodes for the glycogen-branching enzyme (GBE1) located on chromosome band 3p12. The function of this enzyme is to increase the number of branch points during glycogen synthesis. The branched nature of the glycogen molecule is important for its compact nature and solubility within the cell. The absence of this branching activity results in abnormal glycogen with long, unbranched outer chains that resemble amylopectin, which is a glucose polymer that is a major storage polysaccharide in legumes. * Deficient branching enzyme activity and mutations in the gene that encodes for the glycogen-branching enzyme may be generalized or isolated to a specific cell line or tissue. * Specific mutations have been identified in patients with classic, perinatal, and nonprogressive hepatic forms of GSD IV. Further studies to determine genotype-phenotype correlations are in progress.
The differential diagnosis of type IV GSD includes Lafora disease, since the liver biopsy can show similar inclusions. Although the inclusions in this disorder stain positively with the colloidal iron stain, they are not as coarsely clumped as in type IV GSD. Also, patients with Lafora disease typically present in late childhood or adolescence with the characteristic clinical triad of epilepsy, myoclonus, and dementia..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.
There is no specific treatment available for type IV GSD. Orthotopic liver transplantation has resulted in improved patient outcome because metabolic sequelae, such as cardiomyopathy and skeletal myopathy, have not developed in most cases. Postoperative heart biopsies from patients have shown minimal amylopectin deposits up to 4½ years following transplantation. Failure of liver transplantation to diminish cardiac deposits of amylopectin leading to death has been reported3; however, multiorgan transplantation has been suggested in cases with severe multiorgan involvement.