gsd iii var mmr2 11-3
TRANSCRIPT
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A Novel Form of Glycogen Storage Disease (GSD) III Caused by a Variant
Gene
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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.
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Workup
A prior workup 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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Suspecting type VII
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Types
There are 16 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
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GSD Type III
GSD Type VII
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Glycogen Synthesis
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Glycogen Synthesis
Primarily liver 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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Glycogen Degradation
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Glycogen Degradation
Glycogen phosphorylase (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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PFK
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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
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GSD Genetic Screening Panel
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.
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Glycogen DebranchingEnzyme
175 kDa 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
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Type III Glycogen Storage 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)
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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.
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Thank You for Your Kind Attention!