Discuss the pathophysiology of Glycogen Storage Disease with focus on Type I.

(include treatments)

Type I glycogen storage disease is inherited as an autosomal recessive genetic

disorder. An autosomal recessive disorder means two copies of an abnormal
gene must be present in order for the disease or trait to develop. Glycogen
storage disease type I (GSDI) is characterized by accumulation of excessive
glycogen and fat in the liver and kidneys that can result in an enlarged liver and
kidneys and growth retardation leading to short stature.
GSDI is associated with abnormalities (mutations) in the G6PC gene (GSDIA) or
SLC37A4 gene (GSDIB). These mutations result in enzyme deficiencies that block
glycogen breakdown in affected organs causing excess amounts of glycogen and
fat accumulation in the body tissues and low levels of circulating glucose in the
blood. The enzyme deficiency also results in an imbalance or excessive
accumulation of other metabolites, especially lactates, uric acid and fats like lipids
and triglycerides.
The proteins produced from the G6PC and SLC37A4 genes work together to break
down a type of sugar molecule called glucose 6-phosphate.
SLC37A4 produce glucose 6-phosphate translocase. The primary function of
G6PT is to translocate glucose-6-phosphate (G6P) from the cytoplasm into the
lumen of the ER for hydrolysis to glucose and inorganic phosphate (Pi) either by
the liver/kidney/intestine-restricted glucose-6-phosphatase-α (G6Pase-α) or the
ubiquitously expressed G6Pase-β.
G6PC gene provides instructions for making enzyme glucose 6-phosphatase. In
liver, glucose-6-phosphatase catalyses the terminal step of glycogenolysis and
gluconeogenesis. It plays the important role of providing glucose during starvation.
Unlike most phosphatases acting on water-soluble compounds, it is a membrane-
bound enzyme, being associated with the endoplasmic reticulum. The enzyme
releases free glucose into the bloodstream for other organs and tissues to use
The phosphorylation of glucose by glucokinase adds a charged phosphate
group to this molecule. Consequently, G6P cannot cross the cell membrane,
preventing the diffusion of free glucose out of the cells.
Then glucose-6-phosphate is going to accumulate. High levels of glucose-6-
phosphate activates glycogen synthase (enzyme involved in making glycogen)
and inhibits glycogen phosphorylase (enzyme which breaks down glycogen to
glucose). So the overall effect is an increase in glycogen production despite a
hypoglycemic state
Some patients with GSD I may present with hypoglycemia and lactic acidosis in
the neonatal period. However, they are more likely to present at 3 to 6 months of
age with hepatomegaly and/or signs and symptoms of hypoglycemia, including
seizures. Symptoms of hypoglycemia appear with increased intervals between
feeds. Sometimes the infant may remain asymptomatic and would present with an
enlarged liver and protruding abdomen. Those left untreated would develop an
appearance similar to that seen in Cushing’s syndrome such as short stature, round
face, and full cheeks. They have a failure to thrive along with delayed motor
development. Cerebral damage resulting from recurrent hypoglycemic episodes
may lead to abnormal cognitive development. In addition, patients with GSD Ib
present with recurrent bacterial infections due to neutropenia.
GSDI is treated with a special diet in order to maintain normal glucose levels,
prevent hypoglycemia and maximize growth and development. Frequent
small servings of carbohydrates must be maintained during the day and night
throughout the life. Calcium, vitamin D and iron supplements maybe
recommended to avoid deficits. In patients with GSD I, cornstarch has been
used for the treatment of hypoglycemia as its slow digestion provides a steady
release of glucose. This maintains the glucose levels for longer periods of time.
Medications maybe prescribed to lower lipid levels and prevent and/or treat
kidney disease. No specific drug treatment is recommended for GSD type Ia.
Allopurinol (Zyloprim), a xanthine oxidase inhibitor, therapy can reduce uric
acid levels in the blood and prevent occurrence of gout and kidney stones in
adult life.
Hyperlipidemia can be reduced by lipid-lowering drugs (eg, 3-hydroxy-3-
methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors, fibric acid
derivatives). HMG-CoA reductase inhibitors of cholesterol biosynthesis in the
liver are known as statins
Human granulocyte colony stimulating factor (GCSF) may be used to treat
recurrent infections in GSD type Ib patients. Loss of G6PT activity leads to
enhanced ER stress, oxidative stress, and apoptosis that underlie neutropenia
and neutrophil dysfunction in GSD-Ib.
Von Gierke’s Disease
1. Fasting hypoglycemia
2. Lactic acidemia: Glucose is not synthesized from lactate produced in
muscle and liver. Lactate level increases and pH decreases
3. Hyperlipidemia: Block in gluconeogenesis leads to mobilisation fat to
meet energy requirement. This increases free plasma FA & ketone
bodies.
4. Hyperuricemia: Accumulated glucose -6-p diverted to HMP pathway,
leading to increased synthesis of ribose and nucleotides, this enhances
metabolism of purine nucleotides and to uric acid later
5. Massive liver enlargement leads to cirrhosis
6. Children fail to grow
Given small quantity of food at frequent intervals
There are several types of glycogen storage diseases, including:
1. Type I (von Gierke disease): A deficiency in glucose-6-phosphatase leads to
an inability to produce glucose and an excess of glycogen stored in the liver
and other tissues.
2. Type II (Pompe disease): A deficiency in acid alpha-glucosidase leads to an
excess of glycogen stored in muscles, causing muscle weakness and other
symptoms.
3. Type III (Cori disease or Forbes disease): A deficiency in debranching
enzyme leads to an excess of glycogen stored in muscles and the liver.
4. Type IV (Andersen disease): A deficiency in branching enzyme leads to an
excess of abnormal glycogen stored in the liver, muscles, and other tissues.
5. Type V (McArdle disease): A deficiency in muscle glycogen phosphorylase
leads to muscle weakness and fatigue during exercise.
6. Type VI (Hers disease): A deficiency in liver glycogen phosphorylase leads
to an excess of glycogen stored in the liver.
7. Type VII (Tarui disease): A deficiency in phosphofructokinase leads to an
inability to produce glucose and an excess of glycogen stored in muscles.
8. type IX (phosphorylase kinase deficiency) – liver
9. type XI (Fanconi-Bickel syndrome) – liver, kidneys, intestines
The most common types of GSD are types I, II, III and IV, accounting for nearly
90% of all cases. About 25% of patients with GSD are thought to have type I. GSD
types VI and IX can have very mild symptoms and may be underdiagnosed or not
diagnosed until adulthood.
It is important to note that the types of glycogen storage diseases can vary in their
symptoms, severity, and modes of inheritance, and a definitive diagnosis can only
be made by a healthcare provider after conducting a thorough medical evaluation.