The purpose of this study is to investigate 1) the effects of various dietary treatments on disease progression in the glycogen storage diseases (GSD), 2) the molecular basis and genotype-phenotype correlations of glycogen storage disease, 3) the mechanism and treatment of renal disease associated with type 1 GSD and 4) development of recombinant enzyme replacement therapy for GSD type II. Methods: Patients are seen at 3 months and 6-month intervals for diet evaluation, anthropomorphic measurements and serum chemistries. Muscle strength is evaluated by formal muscle testing including Cybex, by EMG and by changes in serum enzymes (CPK, LDH and isoenzymes, SGOT, SGPT). Renal function clearances and factors affecting hyperfiltration are monitored with diet intervention. Changes in size and number of hepatic adenomas are evaluated at 6-month intervals by ultrasound and CT. Alpha 1-fetoprotein is determined every 6 months in patients with adenomas. Skin fibroblasts and lymphoblastoid cells are obtained from GSD patients for analysis of enzyme activity, antibody-reactive materials, and DNA mutations. Results: 1) When diagnosed and treated early, patients with GSD Ia continue to do well; many have normal growth and development and no evidence of hepatic adenomas or renal dysfunction. We have reviewed the indicators for and reported the long-term outcome of liver transplants for GSD Types I, III and IV. We have defined molecular basis of GSD III. 2) At the DNA level, a nonsense mutation (4529i) in homozygous form was seen in a IIIa patient with sever phenotype; and an ethic-specific mutation (4455delT) was found in North African Jewish IIIa patients and a donor splicing site mutation was found in a Japanese patient. Two missense mutation, R864X and R1228X with frequency of 10.3% and 5.2%, respectively were found in both IIIa and IIIb Caucasian patients while two other missense mutations, 17delAG and Q6X were exclusively found in patients with IIIb. Molecular basis of GSD IB has been defined. Two mutants, G339c and 1211delCT appear to be prevalent in caucasian patients. 3) Recombinant human acid alpha-glucosidase (rhGAA) purified from our genetically engineer producing cells, results in metabolic and clinical correction of Pompe disease in a quail model of the disease. Conclusion: An effective dietary treatment is available for patients with GSD I; whether this treatment can prevent all long-term complications of the disease is not clear. Liver transplantations should be considered for patients with GSD who have developed liver malignancy or hepatic failure and for GSD IV patients with the clinical and progressive hepatic form. In patients with GSD III, a genotype-phenotype correlation of patients with and without muscle involvement exists. Success of treating Pompe disease animals suggests that rhGAA is a promising therapy for human Pompe disease. Significance: This study will provide us a better understanding of the long term complications and its pathogenesis in glycogen storage disease. Molecular study provides a non-invasive way of diagnosis of glycogen storage disease and the use of genotype-phenotype correlation helps the predication of the clinical outcome. Prenatal diagnosis of carrier detection can also be accomplished. Enzyme replacement therapy is a potential effective therapy for patients affected with the form of fatal muscle dysfunction called Pompe disease. Future plans include clinical trials of human recombinant acid alpha-glucosidase in Pompe disease patients.
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