GSD III var mmr2 11-3

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!