Glycogen Storage Diseases
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Direct answer
Named after the physicians who first described them, the glycogen storage diseases are inherited blocks in glycogen synthesis or degradation that leave abnormal quantities or abnormal structure of glycogen in liver, muscle or both. Von Gierke disease (type I, glucose-6-phosphatase deficiency) produces hepatomegaly with fasting hypoglycaemia, lactic acidosis, hyperuricaemia and hyperlipidaemia; Pompe disease (type II, lysosomal acid alpha-glucosidase) is a lysosomal disorder with cardiomegaly and hypotonia; Cori disease (type III) affects the debranching enzyme; Andersen disease (type IV, branching enzyme) causes cirrhosis from amylopectin-like glycogen; and McArdle disease (type V, muscle phosphorylase) causes exercise intolerance with a failure of exercise lactate to rise. Most are autosomal recessive except the X-linked phosphorylase kinase deficiency.
What you must remember
- Type I von Gierke: glucose-6-phosphatase deficiency (lb subtypes differ); doll-like facies, protuberant abdomen, fasting hypoglycaemia with lactic acidosis, hyperuricaemia (gout in adolescence), hypertriglyceridaemia; liver and kidney store glycogen.
- Type II Pompe: acid maltase (acid alpha-glucosidase) deficiency — the only lysosomal GSD; infantile form with massive cardiomegaly, macroglossia, floppy infant and early death; enzyme replacement with alglucosidase alfa is now standard of care.
- Type III Cori: debranching enzyme deficiency, limit dextrin storage; milder than type I, fasting ketosis prominent, liver disease may improve with age.
- Type IV Andersen: branching enzyme deficiency, amylopectinosis causing hepatic cirrhosis; the rare and most malignant of the hepatic forms, occasionally presenting as arthropathy in the adult polyglucosan body variant.
- Type V McArdle: muscle phosphorylase deficiency; cramps, exercise intolerance, myoglobinuria after brief intense activity, second-wind phenomenon from compensatory fatty acid and blood glucose use; ischaemic exercise test shows lactate failing to rise.
- Type VI Hers and type IX: liver phosphorylase and phosphorylase kinase defects respectively — type IX is among the commonest and is X-linked; both mild.
- Type VII Tarui: muscle phosphofructokinase deficiency, adding haemolysis because erythrocytes share the enzyme; exercise intolerance like McArdle plus a haemolytic element.
How to work through a hepatomegaly-plus-hypoglycaemia case
A two-year-old from a consanguineous marriage has a grossly enlarged liver, a chubby abdomen and episodes of early-morning lethargy with blood sugars in the thirties milligram per decilitre. Reason through the enzymology: glycogen is abundant but cannot be converted to free glucose — either the debranching step (type III) or the terminal glucose-6-phosphatase (type I) is blocked. Fasting lactate separates them: in type I, glucose-6-phosphate is shunted to glycolysis causing striking lactic acidosis, while in type III lactate is normal or low with ketosis instead. Add hyperuricaemia and hypertriglyceridaemia and type I is confirmed; genetics (SLC37A4 glucose-6-phosphatase translocase in type Ib with neutropenia) refine the subtype.
Management is pure biochemistry applied: uncooked cornstarch feeds at night release glucose slowly and prevent the hypoglycaemia, allopurinol manages urate, and in type Ib granulocyte-colony stimulating factor treats the neutropenia. For the muscle forms, the bedside logic is the ischaemic exercise test and the "second wind" — McArdle patients who pause briefly can resume exercise as fatty acid oxidation and extramuscular glucose take over, a phenomenon few other metabolic diseases show.
Where students slip
Calling Pompe a cytosolic disease costs the mark: acid maltase is lysosomal, which is why it alone among GSDs also features cardiomyopathy and can be diagnosed by dried blood spot enzyme assay used in some newborn screening programmes. Second, students quote McArdle patients as having exercise-induced lactic acidosis — the opposite, a flat lactate response, is the diagnostic signature. Third, remember that muscle lacks glucose-6-phosphatase altogether, so muscle glycogen can never nourish blood glucose; only liver and kidney export free glucose, which is why muscle phosphorylase deficiency causes symptoms without hypoglycaemia.
Frequently asked questions
Which glycogen storage disease is lysosomal?
Type II Pompe disease, from deficiency of lysosomal acid alpha-glucosidase (acid maltase), presenting with cardiomegaly, macroglossia and hypotonia in the infantile form.
Why does von Gierke disease cause lactic acidosis and hyperuricaemia?
Blocked glucose-6-phosphatase diverts glucose-6-phosphate to glycolysis, raising lactate, while both lactate and released purines compete for renal excretion, increasing urate.
What is the second-wind phenomenon of McArdle disease?
After a brief rest, increased fatty acid oxidation and blood-borne glucose permit resumed activity despite absent muscle phosphorylase.
Which tissues can release free glucose from glycogen?
Only liver and kidney, which possess glucose-6-phosphatase; muscle glycogen is strictly for local consumption.
Which GSD causes hepatic cirrhosis?
Type IV Andersen disease, from branching enzyme deficiency, stores poorly branched amylopectin-like glycogen that injures the liver.