Glycogen & Lysosomal Storage Diseases
Missing enzymes that pack sugar and lipids into cells
Glycogen breakdown and where it fails
Normal glycogenolysis. Glycogen phosphorylase clips glucose off the α-1,4 chains as glucose-1-phosphate until it nears a branch point, leaving limit dextrin; debranching enzyme then removes the α-1,6 branches. Glucose-1-phosphate becomes glucose-6-phosphate. The liver removes that phosphate with glucose-6-phosphatase to release free glucose into the blood, whereas muscle lacks the enzyme and burns glucose-6-phosphate in glycolysis. A small fraction of glycogen is degraded inside lysosomes by acid α-1,4-glucosidase.
- Glycogen phosphorylaseReleases glucose-1-phosphate from α-1,4 chains; muscle isoform absent in McArdle (V)
- Debranching enzyme (α-1,6-glucosidase)Removes branches; absent in Cori (III), so limit dextrin builds up
- Glucose-6-phosphataseFrees glucose from the liver; absent in Von Gierke (I)
- Acid α-1,4-glucosidase (acid maltase)Degrades glycogen in lysosomes; absent in Pompe (II)
The high-yield four. Von Gierke (I), Pompe (II), Cori (III), and McArdle (V) are all autosomal recessive. Each blocks glycogen breakdown, so glycogen accumulates in liver and/or muscle. Mnemonic: Very Poor Carbohydrate Metabolism = types I, II, III, V.
The glycogen storage diseases
| Type | Deficient enzyme | Main tissue | Key findings |
|---|---|---|---|
| I — Von Gierke | Glucose-6-phosphatase | Liver | Severe fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia (gout), hyperlipidemia |
| II — Pompe | Lysosomal acid α-1,4-glucosidase (acid maltase) | Heart, skeletal muscle | Hypertrophic cardiomyopathy and cardiomegaly, hypotonia (floppy baby), macroglossia, early death |
| III — Cori | Debranching enzyme (α-1,6-glucosidase) | Liver, muscle | Milder Von Gierke picture with NORMAL blood lactate; limit dextrin accumulates |
| V — McArdle | Muscle glycogen phosphorylase (myophosphorylase) | Skeletal muscle | Exercise intolerance, painful cramps, myoglobinuria, normal blood glucose, second wind |
Von Gierke, explained. Glucose-6-phosphate that cannot be dephosphorylated is trapped in the liver, so fasting glucose collapses and glucagon cannot raise it. The excess glucose-6-phosphate spills into glycolysis (lactate), the pentose phosphate pathway (purines, then uric acid), and lipid synthesis (hypertriglyceridemia). Treatment: frequent oral glucose and cornstarch, and avoidance of fructose and galactose, which also funnel into glucose-6-phosphate.
Cori vs Von Gierke. With only the debrancher missing, gluconeogenesis still works, so blood lactate is normal and the course is milder.
Pompe. Glycogen packs the lysosomes of heart and skeletal muscle — Pompe trashes the Pump. It is both a glycogen storage disease and a lysosomal storage disease.
McArdle. McArdle = Muscle. Exercising muscle cannot mobilize its glycogen, producing cramps and red, cola-colored urine (myoglobinuria), while blood glucose stays normal because liver phosphorylase is intact. Symptoms ease with brief rest as blood-borne fuel arrives (second wind). On the ischemic forearm test, venous lactate stays flat.
Lysosomal storage diseases: the big picture
Mechanism. Each disease lacks a lysosomal enzyme that degrades a particular substrate, which then accumulates inside lysosomes. The two big families are the sphingolipidoses (Tay-Sachs, Gaucher, Niemann-Pick, Fabry, Krabbe, metachromatic leukodystrophy) and the mucopolysaccharidoses (Hurler, Hunter).
Inheritance. Autosomal recessive except the two X-linked recessive diseases, Fabry and Hunter. Tay-Sachs, Niemann-Pick, and Gaucher are more common in Ashkenazi Jewish populations.
I-cell disease. A related trafficking defect: lysosomal enzymes are made normally but never tagged with mannose-6-phosphate in the Golgi, so they are secreted instead of reaching lysosomes. Plasma lysosomal enzyme levels are high; coarse facies, corneal clouding, and restricted joint movement follow.
Sphingolipidoses
| Disease | Deficient enzyme | Accumulates | Key findings |
|---|---|---|---|
| Tay-Sachs | Hexosaminidase A | GM2 ganglioside | Cherry-red macula, progressive neurodegeneration, exaggerated startle, onion-skin lysosomes; NO hepatosplenomegaly |
| Niemann-Pick | Sphingomyelinase | Sphingomyelin | Cherry-red macula, hepatosplenomegaly, foam cells, progressive neurodegeneration |
| Gaucher | Glucocerebrosidase | Glucocerebroside | Hepatosplenomegaly, pancytopenia, bone crises, avascular necrosis, Gaucher cells |
| Fabry (X-linked) | α-Galactosidase A | Ceramide trihexoside (globotriaosylceramide) | Painful peripheral neuropathy, angiokeratomas, hypohidrosis; progressive renal and cardiovascular disease |
| Krabbe | Galactocerebrosidase | Galactocerebroside, psychosine | Peripheral neuropathy, optic atrophy, globoid cells |
| Metachromatic leukodystrophy | Arylsulfatase A | Cerebroside sulfate | Central and peripheral demyelination, ataxia, dementia |
Two infants with a cherry-red macula: normal-sized liver and spleen → Tay-Sachs (hexosaminidase A); hepatosplenomegaly with foam cells → Niemann-Pick (sphingomyelinase). Mnemonic: No man picks (Niemann-Pick) his nose with his sphinger (sphingomyelinase).
Gaucher. The most common lysosomal storage disease. Glucocerebroside fills macrophages, which look like crumpled tissue paper (Gaucher cells) and infiltrate the liver, spleen, and marrow — explaining the hepatosplenomegaly, pancytopenia, and bone crises with avascular necrosis. Treatment: recombinant glucocerebrosidase (imiglucerase).
Fabry. Typical story: a young man with episodic burning pain in the hands and feet, clusters of dark angiokeratomas over the trunk, and proteinuria, with an affected maternal uncle — the X-linked recessive pattern.
Mucopolysaccharidoses
Hurler vs Hunter. Both accumulate the glycosaminoglycans heparan sulfate and dermatan sulfate; the cornea and the inheritance pattern separate them.
| Feature | Hurler | Hunter |
|---|---|---|
| Deficient enzyme | α-L-iduronidase | Iduronate-2-sulfatase |
| Inheritance | Autosomal recessive | X-linked recessive |
| Cornea | Clouding | Clear (NO clouding) |
| Other features | Coarse "gargoyle" facies, developmental delay | Milder course, aggressive behavior |