Glycogen storage disorders: Pathology review

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Glycogen storage disorders: Pathology review



Glycogen storage disorders: Pathology review

USMLE® Step 1 questions

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USMLE® Step 1 style questions USMLE

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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:

 Sodium   140 mEq/L 
 Potassium  4 mEq/L 
 Creatinine   1.3 mg/dL 
 Creatine kinase  645 U/L 
 BUN/Cr  <15 
 Blood   Positive  
 Erythrocytes  0/hpf 
 Leukocytes  2/hpf 
 Fractional excretion of sodium (FENa  >2%  

Electrocardiogram and echocardiogram are unremarkable. Which of the following is the most likely diagnosis? 


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.


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  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
  4. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education / Medical (2019)
  5. "Newborn Screening for Pompe Disease" Pediatrics (2017)

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