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GSD III var mmr2 11-3
- 1. A Novel Formof Glycogen Storage Disease (GSD) III Caused by a Variant Gene
- 2. Patient JC -62 year old female JC is a 62 year old female referred for a 15 pound weight gain after chemotherapy for breast cancer. She reported exercise induced muscle cramps and severe exhaustion.
- 3. Workup A priorworkup revealed hypoglycemia after prolonged fasting, without evidence of insulin resistance. A CT scan of her abdomen was negative for hepatomegaly. Her liver enzymes were not elevated. She had an elevated 24 hour urine creatine excretion (186 mg/24h; repeat = 150; nl = 0-80) with a normal serum creatine (0.7). Her serum (0.77) and urine creatinine (869.6 mg/24h) were normal.
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- 5. Types There are16 classic GSD phenotypes, caused by genetic defects in glycogen synthesis or degradation in liver, muscle and other cells Inborn Error of Metabolism (IEOM) 1/25,000 live births US Severe cases are diagnosed in early childhood Milder cases may go unrecognized into adulthood
- 7. GSD Type III GSDType VII
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- 9. Glycogen Synthesis Primarilyliver and skeletal muscle tissue Myocardium, kidney – minor amounts Granules (muscle)/clusters (liver) Central glycogenin core, glucose polymers radiating spherically outward Hepatic glycogen - for hypoglycemia Muscle glycogen - energy reserve Glycogen synthase - linear a-1,4-glucose chain Branching enzyme hydrolyzes an a-1,4 bond; Transfers the oligoglucose unit; attaches it with a-1,6 bond; creates branch Glycogen synthase extends both branches
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- 11. Glycogen Degradation Glycogenphosphorylase (rate limiting) breaks a-l,4 glycosidic bonds, releasing glucose 1-phosphate from periphery of granule Activated by Epinephrine and Glucagon/ Inhibited by Insulin Glycogen phosphorylase cannot break a- l,6 bonds and stops when it nears the branch point Debranching enzyme hydrolyzes the a- 1,4 bond nearest the branch point; then transfers the oligoglucose unit to the end of another chain; then hydrolyzes the a- 1,6 bond releasing a single glucose from the former branch
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- 13. Case JC- Assessment/Approach 62 yo female with profound muscle weakness/cramps on exercise Elevated urine creatine Normal liver imaging and labs Suspect mild, GSD - type VII because of hypoglycemia, exercise-induced muscle cramps, abnormal muscle biochemistry and the absence of liver abnormalities. Responded to complex carbohydrate, high protein diet and carnitine supplementation. Symptoms of exhaustion, exercise-induced muscle cramps and excess weight improved
- 14. GSD Genetic ScreeningPanel A genetic sequencing screening panel for 21 GSD associated genes was negative for the 16 classical GSDs But identified a heterozygous variant of the AGL gene encoding glycogen de-branching enzyme (GDE) AGL autosomal gene found of chr 1p21 There was a single base pair DNA substitution of adenine for guanine at position 1087. This variant codes an amino acid substitution in GDE at position p.363 in which arginine replaced glycine.
- 16. Glycogen Debranching Enzyme 175kDa monomer, 1532 AA residues Only eukaryotic enzyme with multiple catalytic sites Two catalytic actions N-terminal –glucosyltransferase activity C-terminal – glucosidase activity Third site for glycogen binding An amino acid substitution in GDE at position p.363 would be expected to effect glucosyltransferase activity
- 17. Type III GlycogenStorage Disease AKA: Debrancher Deficiency, Cori Disease, Forbes Disease, Limit Dextrinosis GSD IIIa involves both liver and muscle (~85%) GSD IIIb only liver (~15%) GSD IIIc only muscle glucosidase (very rare) GSD IIId liver and muscle glucosyltransferase (very rare)
- 18. Novel GSD IIId? This patient appears to have a novel GSD IIId (GSD IIId-2?) variant with glucosyltransferase deficiency only impacting muscle This GDE IIId variant is only problematic with higher energy requirements such as exercise.
- 19. Thank You forYour Kind Attention!
Editor's Notes
- #6 MBBS Medicine (Humanity First): Genetic diseases