MOLECULAR MECHANISMS IN GLYCOGEN STORAGE DISEASE TYPE III

Duke University, Durham NC

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Abstract

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 is 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 is to study the relationship between location and type of 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.