gsd iii var mmr2 11-3
TRANSCRIPT
A Novel Form of Glycogen Storage Disease (GSD) III Caused by a Variant
Gene
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.
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.
Suspecting type VII
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
GSD Type III
GSD Type VII
Glycogen Synthesis
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
Glycogen Degradation
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
PFK
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
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.
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
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)
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.
Thank You for Your Kind Attention!