GeneticsTier 1Medical Sciences concept

Glycogen storage diseases - enzyme deficiencies and phenotypes (McArdle, Pompe, Cori, von Gierke)

Core concept

All autosomal recessive (except some rarer subtypes); each blocks glycogen synthesis/breakdown at a different step -- phenotype reflects which tissue depends most on that step
McArdle disease (type V, myophosphorylase deficiency): muscle-specific -- cannot mobilise muscle glycogen for exercise
Von Gierke disease (type I, glucose-6-phosphatase deficiency): liver/kidney -- cannot release free glucose from glycogen or gluconeogenesis at all

Type	Enzyme deficient	Organ	Key feature
I (von Gierke)	Glucose-6-phosphatase	Liver, kidney	Severe fasting hypoglycaemia, lactic acidosis, hepatomegaly -- cannot make free glucose by any route
II (Pompe)	Acid alpha-glucosidase (lysosomal)	Cardiac + skeletal muscle	Cardiomegaly + hypotonia in infantile form -- the one GSD that is also a lysosomal storage disease
III (Cori)	Debranching enzyme	Liver, muscle	Similar to type I but milder, gluconeogenesis intact
V (McArdle)	Myophosphorylase	Skeletal muscle only	Exercise intolerance, cramps, myoglobinuria -- classic "second wind" phenomenon as fatty acid oxidation compensates

McArdle: exercise testing shows failure of lactate to rise with exercise (cannot break down glycogen to produce lactate) -- the discriminating functional test

Trap: distinguishing McArdle (muscle only, normal fasting glucose) from von Gierke (fasting hypoglycaemia, hepatomegaly, lactic acidosis) -- both involve glycogen metabolism but affect completely different organs and present completely differently
Pompe disease is unique among the classic GSDs for being lysosomal (not cytoplasmic enzyme defect) and for combining cardiac and skeletal muscle involvement -- infantile form is rapidly fatal without enzyme replacement therapy (alglucosidase alfa)
Von Gierke management centres on preventing hypoglycaemia: frequent feeds, uncooked cornstarch, avoiding fructose/galactose (cannot be converted to glucose either)

Pompe disease bridges this note and lysosomal storage disease (separate note) -- same organelle-based classification principle, different substrate
McArdle's "second wind" phenomenon parallels other fatty acid oxidation/mitochondrial myopathy presentations, though the underlying defect (glycogenolysis vs beta-oxidation) differs
All are autosomal recessive -- same Hardy-Weinberg carrier-frequency and consanguinity-risk logic applies to counselling

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