Wolman disease (lysosomal acid lipase deficiency)
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An infant presents with vomiting, diarrhea, failure to thrive, and massive hepatosplenomegaly. Abdominal X-ray reveals bilateral adrenal calcifications. Liver biopsy shows lipid-laden macrophages.
AR; LIPA (lysosomal acid lipase)
LDL reaches the lysosome, where lysosomal acid lipase (LAL) frees cholesterol from its ester. That free cholesterol exits through the pathway encoded by NPC1 and NPC2 and reaches the endoplasmic reticulum, which is where the cell measures its cholesterol supply. Without LAL, the cell starves in the middle of plenty:
- Only unesterified cholesterol crosses the lysosomal membrane, so the ester bond traps the load inside.
- Nothing reaches the ER sensor, so the cell reads itself as cholesterol starved while its lysosomes are engorged.
- SREBP-2 fires: HMG-CoA reductase rises (more synthesis) and LDL receptor rises (more uptake). The new LDL lands in the same lysosome that cannot open it, so the storage drives its own resupply.
- The liver exports the surplus as VLDL, giving high LDL, low HDL, and high triglycerides, a panel that mimics familial hypercholesterolemia.
The adrenal cortex stockpiles cholesteryl esters as raw material for steroid synthesis, so it carries the heaviest load, necroses, and calcifies. Contrast Niemann-Pick type C, where cholesterol is freed normally and then cannot leave the lysosome.
- Massive hepatosplenomegaly
- Bilateral adrenal calcifications (pathognomonic)
- Failure to thrive, malabsorption, steatorrhea
- Rapidly fatal in infantile form (death by 6 months-1 year)
- Late-onset form: cholesteryl ester storage disease (CESD), milder, presents with dyslipidemia and hepatomegaly
- Demonstrate deficient lysosomal acid lipase (LAL) activity in leukocytes/dried blood spot (the diagnostic enzyme assay); not on standard newborn screening
- Imaging: bilateral adrenal calcifications on abdominal X-ray/CT (near-pathognomonic in an infant); lipid-laden macrophages on tissue
- Confirm with LIPA molecular testing
- Enzyme replacement therapy (sebelipase alfa), recombinant LAL delivered to the lysosome, which restores hydrolysis at the blocked step; a statin lowers the LDL but leaves the storage untouched
- HSCT has been attempted with limited success
- Supportive care, nutritional support
"WOLMAN": WithOut Lipase, Mineralized Adrenals in Newborn (the bilateral adrenal calcification on abdominal imaging, nearly pathognomonic in an infant).
"LIPA Lipase": the gene LIPA encodes lysosomal acid lipase, which breaks down cholesteryl esters and triglycerides. Without it, lipids accumulate in lysosomes throughout the body.
"Wolman is Worse, CESD is Calmer": both are caused by LIPA mutations. Wolman disease (infantile) has near-zero enzyme activity and is fatal; CESD (late-onset) has residual activity and a milder course with dyslipidemia.