Purpose: The long term objectives of the proposed research is to obtain a more complete understanding of the phenotype of different forms of glycogen storage disease type III (GSD-III), to identify mutations responsible for the disease, to help predict the clinical outcome and develop a new treatment strategy for the disease. In type III glycogen storage disease there are patients with deficient debranching enzyme activity in both liver and muscle (IIIa) and patients with deficiency in the liver but not the muscle (IIIb) yet the enzyme is a monomeric protein and appears to be identical in all tissues. The disease is characterized by hepatomegaly and/or progressive myopathy for which there is currently no effective treatment. Patients with this disease vary remarkably, both clinically and enzymatically. Although liver symptoms improve with age, muscle symptoms, which are minimal in childhood, increase in the third or fourth decade of life. There is a remarkable clinical variability even within the subgroup of patients who develop myopathy/cardiomyopathy, with no way to accurately predict the progression of the disease at the present time. We have identified exon 3 mutations in GSDIIIb patients. We hypothesize that mutations in GSD IIIb patients will shed light in the tissue specific expression of the debrancher gene.
The second aim i s to delineate the phenotype and clinical course within subtypes of GSD III through liver, muscle and cardiac studies. We hypothesize that patients with GSD IIIb will not develop muscle disease.
The third aim i s to study the relationship between location and type pf mutations in GSD III patients to the subtype and clinical severity of the disease. We hypothesize that the clinical outcome can be predicted in part based on the molecular definition.
The fourth aim i s to test the feasibility of enzyme replacement therapy for the disease by treating type III GSD patient cells in vitro with acid alpha-glucosidase (GAA). Methods Identification and characterization of mutations in different forms of GSD III will be done by SSCP followed by DNA sequencing. To better delineate phenotype and clinical course of the disease within subtypes of GSD III, detailed studies are performed on liver ( liver function tests, abdominal CT). Muscle studies to assess muscle strength and detailed cardiac studies (Holter and Echo) are being performed on all subjects. We are exploring the relationship between location and type of mutations in GSD III to subtype the clinical severity of the disease. Results (12/97 TO 12/98) 7 patients, 5M:2F ( 3 1/2 years -64 years), have been evaluated on this protocol. Of these patients, 6 are Caucasian, and one is African-American. 6 patients have GSD IIIa and one GSDIIIb. No adverse or unusual reactions were noted. After detailed muscle testing by the physical therapist involved in the project, it was found that all 6 subjects with GSDIIIa had myopathy. Subtle changes which may not have been identified by routine muscle testing were identified in 2/6 patients by the method (muscle dynamometry) used by us. Physical therapy has been initiated. 3/6 patients were also found to be deficient in carnitine, (documented for first time in this disease) and have since been started on carnitine. No changes on 24-hour holter monitor were found in the 6 patients. Significance and Future Plans Information gained by analysis of the debrancher gene and clinical and molecular dissection of different subtypes of GSD III will provide insight into patient phenotype, the molecular basis of the disease, functional domains for the multifunctional enzyme, and general mechanisms controlling tissue-specific gene expression. Experiments with enzyme replacement therapy in vitro represents the first step in an overall program to develop an effective treatment for type III.
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