Glycogen storage disease type I

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Glycogen storage disease type I, also called Von-Gierke’s disease, is a genetic disorder caused by a mutation in the glucose 6 phosphatase gene on chromosome 17.
The end result is that glycogen can’t be broken down into glucose in liver cells, so glucose metabolism goes awry, resulting in symptoms like low blood sugar, weakness and poor growth.
Glucose is such an important energy source, that our body stores excess glucose in liver cells and skeletal muscle cells in the form of glycogen.
Glycogen is basically an enormous molecule or polymer, that’s made up of glucose molecules linked together by glycosidic bonds.
And glycogen has a main chain, as well as multiple branches sprouting off of it. These branches allow glycogen to be compact and also allow it to rapidly add and remove glucose to and from the big glycogen molecule.
Talk about a molecular sugar rush! Now, glucose molecules are usually added to glycogen in response to insulin, which is secreted by the pancreas after meals.
That’s when there’s high blood sugar, or plenty of glucose floating around in the bloodstream. So, it makes sense for some of this glucose to be stored as glycogen, right?
Now when it’s been a while after a meal, so when you’re fasting, blood sugar levels take a dip. In response, the pancreas secretes glucagon and the adrenal glands secrete epinephrine.
It turns out that glucagon tells the liver cells to break glycogen down into individual glucose molecules, and epinephrine tells skeletal muscle cells to do the same.
In both the liver and skeletal muscle cells, glycogen breakdown begins with the branches, and it results in the release of glucose-6-phosphate - which is just like glucose, but with a phosphate clinging to it.
In liver cells, an enzyme called glucose-6-phosphatase removes the phosphate off of the 6th carbon, releasing free glucose into the bloodstream, for all the organs and tissues to enjoy - very generous!
Skeletal muscle cells, on the other hand, can simply use glucose-6-phosphate for energy - but they lack glucose 6 phosphatase, so they don’t share any of it with other organs and tissues!
Now with glycogen storage disease type I, there’s not enough glucose 6 phosphatase, so glucose-6 phosphate can’t get that phosphate molecule cleaved off and become glucose, so it can’t leave liver cells for fasting energy.
But liver cells have plenty of biochemical pathways all working hard at the same time, so glucose-6-phosphate can be used to make something else instead.
So first, glucose-6-phosphate can be shunted towards glycolysis, which is the biochemical pathway that uses glucose-6-phosphate to make pyruvate and acetyl-CoA.
Pyruvate then becomes lactic acid, and when a lot of lactic acid is generated, it can lower blood PH enough to cause lactic acidosis.
When a lot of acetyl-CoA molecules are generated, they can be joined together to form free fatty acids, which are then used to make triglycerides.
In time, this may cause hypertriglyceridemia and hyperlipidemia. Alternatively, glucose-6-phosphate can embark on a long journey called the pentose phosphate pathway, where it becomes ribose-5-phosphate, a uric acid precursor.
In time, excess uric acid causes hyperuricemia. Now, glycogen storage disease type I is an autosomal recessive disorder, so a person needs to inherit two copies of the mutated gene, one from each parent, to develop the condition.
And if they do, symptoms present early on, between 3 to 6 months of age. They include neurological abnormalities like seizures, lethargy and weakness, which result because the metabolically active brain gets starved of glucose during episodes of hypoglycemia.
Other features include growth delay or developmental delay, and there may also be hepatomegaly, on account of glycogen buildup in the liver.
When Von-Gierke’s disease is suspected, diagnosis can be confirmed by DNA testing which looks for mutations in the genes on chromosome 17 that code for glucose-6-phosphatase.
Treatment for Von-Gierke’s disease is complex, and involves a team of physicians and other specialized dietary and endocrine practitioners.
In general, treatment is aimed at controlling the metabolic derangements associated with this disorder. For hypoglycemia, patients consume a diet of complex carbohydrates frequently and avoid products with fructose and galactose, like soda, or juices.
This is because these compounds are intermediately digested to glucose-6-phosphate before being used for energy in the form of glucose.
If a person presents with severe hypoglycemia, IV dextrose can be given, which will help to correct the low blood sugar and any co presenting lactic acidosis.
Additionally, people with lactic acidosis can receive bicarbonate. Statins or fibrates can be used to correct lipid imbalances.
All right, as a quick recap… glycogen storage disease type I, or Von Gierke’s disease, happens because of a genetic mutation on chromosome 17, which results in glucose-6-phosphatase deficiency.
The symptoms include severe fasting hypoglycemia, other metabolic abnormalities, an enlarged liver, and growth delay. The treatment of Von-Gierke’s disease is multifactorial and primarily involves controlling blood sugar levels.