Glycogen Storage Diseases

Tempting to pick debranching enzyme deficiency since it also causes hepatomegaly and hypoglycemia and sounds structurally similar, but the severity of the metabolic overflow (lactic acidosis, hyperuricemia, hypertriglyceridemia) points to a complete exit block for glucose, not a partial one. Think of G6Pase as the factory's only exit door for glucose: without it, glucose-6-phosphate backs up in the warehouse and workers start loading it onto every other outbound truck available (glycolysis to lactate, pentose shunt to uric acid, lipogenesis to triglycerides). Correct: B

Von Gierke disease (GSD Ia). G6Pase is required for the final step of BOTH glycogenolysis and gluconeogenesis. Without it, glucose-6-phosphate cannot be converted to free glucose. G6P shunts into glycolysis (lactic acidosis), pentose phosphate pathway (purines to uric acid), and lipogenesis (hypertriglyceridemia).

Break it down: Debranching enzyme deficiency (Cori, GSD III) gives milder hypoglycemia and normal lactate. Liver phosphorylase (Hers, GSD VI) causes mild benign hepatomegaly without the metabolic overflow. Branching enzyme (Andersen, GSD IV) causes cirrhosis, not hypoglycemia.

Tempting to say increased glycolysis explains the second wind since glucose is available in the bloodstream and GLUT4 uptake is intact in McArdle, but local glucose oxidation alone cannot compensate for the failed muscle glycogenolysis. Think of the McArdle muscle as a factory with a locked internal fuel tank (glycogen): when the emergency reserves run out, the plant halts until an external delivery truck arrives (hepatic glucose output) and a second fuel source activates (fatty acid oxidation). That external resupply IS the second wind. Correct: C

McArdle disease (GSD V). Muscle phosphorylase is absent, so skeletal muscle cannot break down its own glycogen. During the first minutes of exercise, available ATP from phosphocreatine and circulating glucose is consumed, causing cramps. The "second wind" occurs because after a brief rest, the liver increases glucose output and fatty acid oxidation ramps up in muscle. Both of these fuel sources bypass the glycogenolysis block entirely.

Break it down: Glycolysis can run on incoming glucose but still can't supplement from glycogen. GLUT4 translocation is intact in McArdle, meaning glucose can enter the cell, but the total fuel delivery from the liver is limited and delayed. Pyruvate carboxylase is a gluconeogenic enzyme in liver and doesn't apply here.

Tempting to pick imiglucerase since Gaucher disease is the most tested lysosomal storage disease with enzyme replacement therapy, but imiglucerase replaces glucocerebrosidase, not acid maltase. Think of lysosomal storage diseases as different warehouses with different broken forklifts: you have to send the exact replacement model. Alglucosidase replaces acid maltase (Pompe's broken forklift); imiglucerase replaces glucocerebrosidase (Gaucher's broken forklift). The cardiac-predominant floppy infant with normal glucose tells you which warehouse you are in. Correct: B

Pompe disease (GSD II). The massive cardiomegaly in a floppy infant with hypotonia and normal glucose is the pathognomonic presentation. Acid alpha-1,4-glucosidase (acid maltase) deficiency causes glycogen accumulation in lysosomes of all tissues, with the heart and skeletal muscle most severely affected. Alglucosidase alfa (Lumizyme/Myozyme) is the approved enzyme replacement therapy.

Break it down: Imiglucerase treats Gaucher disease (glucocerebroside accumulation). Idursulfase treats Hunter syndrome (MPS II, iduronate sulfatase deficiency). Laronidase treats Hurler syndrome (MPS I, alpha-L-iduronidase deficiency). The normal glucose and cardiac-predominant presentation with normal liver size distinguish Pompe from all liver-based GSDs.

Tempting to pick debranching enzyme since both Cori and Andersen affect glycogen branch structure and both cause liver disease, but Cori causes milder disease without cirrhosis while Andersen's abnormal amylopectin-like glycogen triggers a hepatic foreign-body inflammatory response. Think of Andersen's unbranched glycogen as delivering tree logs instead of properly chopped firewood to the liver's furnace: the logs cannot be processed, pile up as foreign material, and the liver's immune cells attack them progressively until fibrosis sets in. Correct: C

Andersen disease (GSD IV). Branching enzyme deficiency results in glycogen with abnormally long, poorly-branched chains that resemble plant amylopectin. This structurally abnormal glycogen is treated as a foreign body by the liver, triggering progressive inflammation, fibrosis, and cirrhosis. Liver failure in childhood is the result without transplant.

Break it down: Muscle phosphorylase (McArdle, GSD V) causes exercise intolerance with myoglobinuria, not cirrhosis. Glucose-6-phosphatase (Von Gierke) causes severe hypoglycemia and massive hepatomegaly, but NOT cirrhosis. Debranching enzyme (Cori, GSD III) causes partial glycogenolysis with milder liver disease, myopathy, and normal lactate.