1. Glycogen Storage Diseases
By: Borar Som, Jennifer Nguyen, Jeremy Rousse-Grossman, Nora Wahib
PHM Fall 2017
Instructor: Dr. Jeffrey Henderson

2. Glycogen Chain polymer of glucose Branched
α-1,6 and α-1,4 linkages
Stores glucose in liver, skeletal muscle, and cardiac muscle
Nora’s Slide

3. Glycogen Synthesis and Breakdown

4. Glycogen Storage Disease
Overview
Genetic GSD*: Genetic mutations which lead to enzyme deficiencies
Result in excess glycogen accumulation in liver and/or muscle tissue
Divided into subtypes based on specific enzyme effected (0-XV)
Jeremy’s Slide

5. Clinical Presentation
Based on location of glycogen accumulation (liver vs. muscle)
Liver (Types Ia, Ib, III, IV, VI, IX)
Hepatomegaly, Cirrhosis, Hypoglycemia, Failure to Thrive, elevated lactate and urate (+/- neutrophil dysfunction)
Muscle (Types II, III, X)
Elevated Creatine Kinase, Muscle Weakness, Hypertrophic Cardiomyopathy (+/- Rhabdomyolysis)

6. Glycogen Storage Disease – Type III
Cori’s or Forbes Disease
Affects the Liver, Skeletal Muscle, and Heart
Activity deficiency of Glycogen Debranching Enzyme (GDE)
Subtypes:
IIIa – Liver and Muscle
IIIb – Liver only
IIIc – Muscle only
IIId – Liver and Muscle
Borar’s Slide
IIIa – Liver and Muscle
Both enzyme activities affected in both liver and muscle tissue
IIIb – Liver only
Both enzyme activities in only liver tissue
IIIc – Muscle only
The activity of 1 of the 2 activities of the enzyme (glucosidase) is lost and only affects muscle tissue
IIId – Liver and Muscle
Only the activity of the other GDE activity (glycotransferase) is lost, but affects both liver and muscle

7. Glycogen Debranching Enzyme (GDE)
Two separate catalytic sites, GC and GT
GC – glucosidase
GT – glycosyltransferase
Catalytic domains are independent
Both have important implications on glycogen catabolism
My slide
Zhai, Liting, et al. "Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations." Nature Communications, vol. 7, 18 Apr. 2016, pp

8. Glycogen Debranching Enzyme (GDE) Cont’d…
Glycogen phosphorylase (GP) breaks off monomers
Branch has 3-4 monomers left, GDE comes into play
GT removes terminal monomers, leaving a single branched monomer
GC removes branch point
Purple chain can then be broken down

9. Common Mutations and Genetics
Enzyme has 4 mRNA isoforms but a single protein
Exon 3 mutations common to type IIIb
Retained function in muscle
Common mutations: 17delAG and C16T
Severely truncated protein
My Slide
Shen, Jianjun, et al. "Mutations in Exon 3 of Glycogen Debranching Enzyme Gene Are Associated with Glycogen Storage Disease Type III That Is Differentially Expressed in Liver and Muscle." Journal of Clinical Investigation, vol. 98, no. 2, July 1996, pp

10. Treatment and Symptom Management
Hypoglycemia
Diet
Carbohydrate rich
Protein rich (gluconeogenesis)
Liver transplant
End-stage of liver cirrhosis and/or carcinoma
Not specifically for treating the metabolic deficit
Currently no treatment for myopathy
Nora and Jeremy

11. Future Research Alternative energy sources
Suppression of Glycogen Accumulation
Gene therapy
Challenge: 5 kb GDE Expression Cassette > 4.7 kb AAV Vector
Potential Solution: Use Hybrid-Dual AAV
Further studies in Tissue Specific Protein Expression
Borar

12. Summary Two separate catalytic sites, GC and GT
GC – glucosidase
GT – glycosyltransferase
Catalytic domains are independent
Both have important implications on glycogen catabolism
My slide
Zhai, Liting, et al. "Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations." Nature Communications, vol. 7, 18 Apr. 2016, pp

13. Summary Glycogen phosphorylase (GP) breaks off monomers
Branch has 3-4 monomers left, GDE comes into play
GT removes terminal monomers, leaving a single branched monomer
GC removes branch point
Purple chain can then be broken down

14. Summary
Glycogen is a branched, chain polymer of glucose that is used for the storage of glucose in the Liver, Skeletal Muscle, and Cardiac Muscle
Glycogen Storage Diseases are caused by enzyme deficiencies or deficiencies in enzyme activity in the storage/breakdown pathway of Glycogen
Symptoms of GSD Type III are due to the deficient activity of Glycogen Debranching Enzyme (GDE), which has 2 independent catalytic domains
GSD Type III is caused by an recessive autosomal mutation
Treatments are for symptoms management only

15. References
Christian, Hendriksz J., and Gissen Paul. "Glycogen storage disease." Paediatrics and Child Health, vol. 21, no. 2, Feb. 2011, pp
Kishnani, Priya, et al. "Glycogen Storage Disease Type III diagnosis and management guidelines." Genetics in Medicine, vol. 12, no. 7, July 2010, pp
Patrick, McKiernan. "Pathobiology of the Hepatic Glycogen Storage Diseases." Current Pathobiology Reports, vol. 5, pp
Shen, Jianjun, et al. "Mutations in Exon 3 of Glycogen Debranching Enzyme Gene Are Associated with Glycogen Storage Disease Type III That Is Differentially Expressed in Liver and Muscle." Journal of Clinical Investigation, vol. 98, no. 2, July 1996, pp
Sun, Baodong, et al. "Preclinical Development of New Therapy For Glycogen Storage Diseases." Current Gene Therapy, vol. 15, no. 4, 2015, pp
Wolfsdorf, Joseph I., and David A. Weinstein. "Glycogen Storage Diseases." Reviews in Endocrine & Metabolic Disorders, vol. 4, no. 1, 2003, pp
Zhai, Liting, et al. "Crystal structure of glycogen debranching enzyme and insights into its catalysis and disease-causing mutations." Nature Communications, vol. 7, 18 Apr. 2016, pp