Glycogen storage disorders: Pathology review

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Case study0:00–1:14

5-year-old Manthos is brought to the emergency department by his mother due to recurring episodes of losing consciousness, accompanied by sweating and pallor.
Manthos’ mother also mentions that symptoms tend to be worse when he wakes up, and decreases after meals. Physical examination reveals fat, rounded cheeks, relatively thin extremities, and a protuberant abdomen.
Upon palpation of the abdomen, the liver is found to be enlarged. Laboratory studies are obtained, showing a glucose level of 40 milligrams per deciliter or 2.2 millimoles per liter, a triglyceride level of 200 mg/dl or 5.1 mmol/L, and a lactic acid level of 3.1 milligrams per deciliter or 0.34 millimoles per liter.
Some days later, 3-month-old Becca is brought to the office by her parents, who complain that she’s been having problems feeding.
Based on her history, Becca has also failed to reach the appropriate motor and cognitive developmental milestones. Physical examination reveals reduced muscle tone, and echocardiography shows an enlarged heart.Based on the initial presentation, both Manthos and Becca seem to have some form of glycogen storage disease.

Physiology1:14–3:52

Okay, but first a bit of physiology. Glycogen is made up of a main chain, where glucose molecules are linked by alpha 1,4 glycosidic bonds, and multiple branches, each of which is connected to the main chain by alpha 1,6 glycosidic bonds.
When glucose enters the cells, it is turned into glucose-6-phosphate, which can either be used to make ATP through glycolysis or turn into glycogen.
This process is called glycogenesis and occurs mainly in liver and muscle cells. To do that, an enzyme called phosphoglucomutase turns glucose-6-phosphate into glucose-1-phosphate, which is then converted into UDP-glucose by UDP-glucose pyrophosphorylase.
UDP-glucose is then attached by glycogen synthase to a glucose residue at the end of the glycogen branch, forming an alpha 1,4 glycosidic bond.
Finally, the glycogen-branching enzyme adds branches by creating an alpha 1,6 glycosidic bond. Okay, but then comes glycogenolysis, which is when glycogen is broken down into individual glucose molecules.
In both the liver and muscle cells, glycogen phosphorylase starts by cleaving the alpha 1-4 bonds, releasing one glucose-1-phosphate at a time.
Next, a debranching enzyme, also called alpha-1,6-glucosidase, cleaves off the alpha 1-6 bond and releases a free glucose-1-phosphate, which then gets converted to glucose-6-phosphate by phosphoglucomutase.
Now, keep in mind that, in muscle cells, glycogen breakdown also takes place inside of a lysosome. That’s where a lysosomal enzyme called acid maltase has both α-1,4- glucosidase and α-1,6- glucosidase activity, chopping off glucose molecules from glycogen.
Another difference between the liver and muscles is that liver cells have an enzyme called glucose-6-phosphatase that removes that phosphate, releasing free glucose into the bloodstream.
Muscle cells, on the other hand, don't have this enzyme, so they simply use the glucose-6-phosphate to make ATP via the glycolysis pathway.
Now, there are a total of 15 subtypes of glycogen storage disease, all of which result in the inability of the body to either break down or synthesize glycogen.
For your exam, the most high yield ones are types I, II, III, and V. Remember that these are all autosomal recessive diseases, meaning that an individual needs to inherit two copies of the mutated gene, one from each parent, to develop the condition.

Pathology3:52–4:20

Okay, let’s start with glycogen storage disease type I, also known as von Gierke disease. This occurs when glucose 6 phosphatase is deficient, so glucose-6-phosphate can’t be turned into free glucose and then get released by liver cells into the bloodstream.

von Gierke disease4:20–8:12

Now, this is also the final step of gluconeogenesis, where glucose is made from other molecules like amino acids and glycerol.
So, remember that von Gierke disease affects both glycogenolysis and gluconeogenesis, and the result is hypoglycemia, especially during fasting.
Now, glucose-6-phosphate can be shunted towards glycolysis, to make pyruvate and acetyl-CoA. Pyruvate can then become lactic acid, and if that builds up, it can result in lactic acidosis.
Acetyl-CoA molecules can be joined together to form free fatty acids, which are then used to make triglycerides. Over time, this may lead to hypertriglyceridemia and hyperlipidemia.
For your exams, remember that this hyperlipidemia is also associated with low levels of insulin. That’s because normally, insulin increases lipid uptake in adipose tissue by stimulating lipoprotein lipase to release fatty acids from VLDL and chylomicrons in the bloodstream.
In von Gierke disease, prolonged hypoglycemia causes insulin levels to eventually drop, resulting in decreased lipoprotein lipase activity.
So now large amounts of VLDL particles stay in the blood instead of being broken down and stored, and these eventually get converted to LDL.
Okay, now, instead of glycolysis, glucose-6-phosphate can also embark on the pentose phosphate pathway, where it becomes ribose-5-phosphate, a uric acid precursor.
Over time, excess uric acid can lead to hyperuricemia or gout. Symptoms of von Gierke disease typically include neurological abnormalities like loss of consciousness, sweating, pallor, seizures, lethargy, and episodes of hypoglycemia.
A clue to keep in mind is that these episodes tend to be worse during fasting and improve after meals, when there’s plenty of glucose around.
Other features include growth or developmental delay, as well as hepatomegaly and renomegaly due to glycogen buildup in the liver and kidneys.
In a test question, these individuals will classically be described as having “doll-like faces” with fat rounded cheeks, protuberant abdomen, thin extremities, and short stature.Diagnosis can be confirmed by genetic testing, which looks for mutations in the genes that code for glucose-6-phosphatase.
Additionally, a liver biopsy with periodic acid-Schiff stain or PAS can help confirm large quantities of glycogen in liver cells.
Treatment of von Gierke disease is aimed at controlling its metabolic dysfunction. For hypoglycemia, individuals require a diet rich in complex carbohydrates.
Remember that these individuals need to 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. Additionally, people with lactic acidosis can receive bicarbonate.
Finally, statins or fibrates can be used to correct lipid imbalances.Next is glycogen storage disease type II, also known as Pompe disease.
This results from a deficiency of lysosomal acid maltase, which causes glycogen to accumulate in the lysosomes of skeletal muscle, smooth muscle, and cardiac muscle cells.
As a consequence, these lysosomes can’t degrade the cell’s waste material, which ends up accumulating in the cytoplasm and impairing muscle cell contraction.

Pompe disease8:12–10:25

Over time, glycogen accumulation can lead to lysis, or rupture, of lysosomes. And since lysosomes contain degradative enzymes, if these get released, they can destroy the whole cell.Now, the symptoms of Pompe’s disease involve the heart, skeletal muscle, and smooth muscle.
For your exams, make sure to remember that the most classic finding is cardiomegaly or hypertrophic cardiomyopathy, meaning a large heart that can’t pump blood effectively.
A good way to remember this is Pompe affects the pump. In skeletal muscle, the disease can cause macroglossia or tongue enlargement, weakness, low muscle tone, pain with exercise, and difficulty breathing or even respiratory failure.
And that’s the reason why most individuals die within the first 5 years of life. Other high-yield abnormalities include feeding difficulty because of damaged smooth muscle in the gastrointestinal tract, which eventually causes failure to thrive.Diagnosis of Pompe’s disease is done by genetic testing, looking for mutations in the acid maltase gene.
Additional tests that can solidify the diagnosis include elevated blood levels of creatinine kinase, which is a protein normally found in muscle cells that leaks into the blood when these are destroyed.
Finally, a muscle biopsy with periodic acid schiff stain or PAS can help identify the glycogen accumulation in lysosomal vesicles.
For treatment, enzyme replacement therapy is available, which means an injection of recombinant acid maltase is given every two weeks.
Moving on, glycogen storage disease type III, also known as Cori disease. It occurs when the debranching enzyme or alpha-1,6-glucosidase is deficient.
So, just like von Gierke disease, you’re gonna get hypoglycemia because the liver is still unable to release glucose from glycogen into the bloodstream.

Cori disease10:25–12:33

However, remember that hypoglycemia in Cori disease is typically milder than that of von Gierke disease. And that’s because gluconeogenesis remains unaffected.
Another difference is that it’s not glucose-6-phosphate that builds up, so there’s no lactic acidosis or hyperuricemia. Instead, Cori disease will have an accumulation of incompletely broken down glycogen inside the liver and muscle cells.
A very high yield fact is that you can look for a buildup of limit dextrins which are intermediate products of glycogen breakdown with short branches at their ends that cannot be degraded.
Another thing to keep in mind is that there might be mild hypertriglyceridemia or hyperlipidemia due to the constantly low insulin levels.
Now, symptoms of Cori disease mainly include those associated with mild episodes of hypoglycemia, including loss of consciousness, weakness, sweating, or pallor.
Hepatomegaly develops due to the glycogen buildup. Less commonly, skeletal and cardiac muscle can also be affected, resulting in hypotonia, exercise intolerance, and cardiomyopathy.
Diagnosis can be confirmed by genetic testing, looking for the mutation in the gene that codes for the debranching enzyme, along with a liver or muscle biopsy with PAS stain.
Treatment involves consuming a diet rich in complex carbohydrates. Remember that unlike von Gierke disease, products with fructose and galactose don’t need to be avoided, since there’s no problem with glucose-6-phosphate.Okay, now, glycogen storage disease type V, also known as McArdle disease, results from a lack of glycogen phosphorylase in skeletal muscle, so remember McArdle for Muscle.
What this means is that muscle cells can’t break down glycogen into glucose-1-phosphate to obtain glucose. The important thing to note though is that this will not result in hypoglycemia, since muscle cells don’t release glucose into the bloodstream, but keep it for themselves.

McArdle disease12:33–15:33

The problem is that they won’t be able to use that glycogen for energy, especially during strenuous exercise. Instead, glycogen is going to accumulate in muscle cells, eventually causing them to die, which is known as rhabdomyolysis.
This will let their cellular contents get released into the bloodstream. Buildup of various electrolytes, such as potassium and phosphate, cause hyperkalemia and hyperphosphatemia.
Proteins like myoglobin, will end up getting extracted in the urine, causing myoglobinuria. Now, another high-yield characteristic of McArdle disease is that, after exercise, lactate levels remain steady in the venous blood, in contrast to ammonia levels, which will rise normally.
This is thought to be due to increased uptake of lactate through a protein called monocarboxylate transporter, or MCT1, which has been found to be upregulated in the skeletal muscles of individuals with McArdle.
On top of that, that lactate might actually be useful for those skeletal muscles, since they could convert it to pyruvate and use it as an alternative energy source.
On the other hand, ammonia levels rise normally, probably because ammonia is a byproduct of the adenylate kinase pathway, which provides another alternative pathway for ATP production.Symptoms of McArdle disease are more prominent during strenuous exercise and include muscle cramping, fatigue, and red urine due to myoglobinuria.
Now, in a test question, a telltale sign for McArdle disease is the so-called “second wind phenomenon”, meaning that symptoms of muscle fatigue might get better after about 10 minutes of exercise.
That’s probably related to the increased blood flow to the muscles during exercise, which allows them to compensate for the impaired glycogen breakdown by getting alternative sources of energy, like fatty acids and proteins.
Individuals might also experience arrhythmias due to electrolyte disturbances.Diagnosis can be confirmed by genetic testing, looking for the mutation in the gene that codes for the skeletal muscle glycogen phosphorylase enzyme.
A muscle biopsy may also be done to show the glycogen buildup with a PAS stain, as well as the absence of myophosphorylase.
Treatment for McArdle disease once again focuses on the frequent dietary consumption of complex carbohydrates.Alright, as a quick recap, glycogen storage disease type I or von Gierke disease results from a deficiency of glucose-6-phosphatase, affecting both glycogenolysis and gluconeogenesis in the liver and kidneys.
This presents with severe fasting hypoglycemia, hyperlipidemia, hyperuricemia, and lactic acidosis, as well as fat, rounded cheeks, protuberant belly, hepatomegaly and renomegaly.
Glycogen storage disease type II or Pompe disease, results from a deficiency of lysosomal acid maltase, which affects the cardiac, skeletal and smooth muscles, causing cardiomegaly, macroglossia, hypotonia, difficulty breathing and feeding, and failure to thrive.

Review15:33–16:57

Glycogen storage disease type III or Cori disease, results from a deficiency of the debranching enzyme, which affects glycogenolysis in the liver and muscle, and can present with mild hypoglycemia and hyperlipidemia, as well as hepatomegaly and cardiomyopathy.
Glycogen storage disease type V or McArdle disease, results from a deficiency of glycogen phosphorylase in the skeletal muscles.
This can present with muscle weakness and exercise intolerance with a second wind phenomenon, myoglobinuria, and arrhythmias due to hyperkalemia and hyperphosphatemia.Okay, back to our cases.
Manthos is the 5-year-old boy who presented recurring episodes of losing consciousness. As well as sweating and pallor, which are worse during fasting and improve after meals, classic findings of hypoglycemia.
He has the typical physical appearance of a doll-like face, thin extremities and a protuberant abdomen. This combined with the hepatomegaly on palpation, and the lab studies showing hypoglycemia, hypertriglyceridemia and lactic acidosis, all point to von Gierke disease.
Genetic testing confirmed the mutation in glucose-6-phosphatase gene. On the other hand, Becca, the 3-month-old girl, came in with some very generic symptoms like feeding difficulty, and developmental delay.

Summary16:57–17:58

However, she also had cardiomegaly, which combined with the other symptoms should make you suspect Pompe disease. Diagnosis was confirmed with genetic testing showing a defect in the lysosomal acid maltase gene.
protuberant abdomen. This combined with the hepatomegaly on palpation and the lab studies showing hypoglycemia hypertriglyceridemia and lactic acidosis.
All Point Devon gierke disease. Genetic testing confirmed the mutation in the glucose 6, phosphatase Gene.
On the other hand. Got the three month old girl came in with some very generic symptoms like feeding difficulty and developmental delay.
However, she also had cardiomegaly which combined with the other symptoms should make you suspect pompe disease. Diagnosis, was confirmed with genetic testing showing a defect in the lysosomal acid,