AssessmentsGlycogen storage disorders: Pathology review
USMLE® Step 1 style questions USMLE
A 20-year-old man comes to the emergency department with painful muscle spasms. He notices that these episodes worsen after a run and seem to improve after brief periods of rest. His past medical history includes a right knee ACL tear. His temperature is 37.0°C (98.6°F), pulse is 80/min, respirations are 16/min, and blood pressure is 125/75 mmHg. Abdominal examination is unremarkable. Rapid fingerstick glucose is 80 mg/dL. Serum creatine kinase levels are elevated. Laboratory investigations are shown below:
|Creatine kinase||645 U/L|
|Fractional excretion of sodium (FENa)||>2%|
Electrocardiogram and echocardiogram are unremarkable. Which of the following is the most likely diagnosis?
Content Reviewers:Antonella Melani, MD
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. 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.
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. 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. 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.
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