NQ-117: (B) X-linked adrenoleukodystrophy

Pathology of the case: The adrenal glands are usually small and atrophic. Histologically, the zona glomerulosa is preserved but the cells in zona fasiculata and reticulata are enlarged, secondary to the accumulation of cytoplasmic birefringent striation. X-linked adrenoleukodystrophy (X-ALD) is a disorder of peroxisomal fatty acid beta oxidation resulting in the build up of very long chain fatty acids (VLCFAs) within the body. This accumulation results in demyelination with macrophage infiltration and adrenal insufficiency. Lamellar cytoplasmic inclusions (image) may be seen in the cells of the adrenal cortex. [Click here to see online information about x-ALD]

• Lipid lamellae: The lipid storage material stain poorly with traditional lipid stains. Under EM, the adrenal striations contain lamellae and lamellar lipid profiles. These lamellae are non-specific for X-ALD since they are also seen in other peroximal disorders including Zellweger syndrome, neonatal ALD, and infantile Refsum’s disease. These lipid droplets are seen in the cytoplasm of Schwann cells, testicular interstitial cells, liver, CNS macrophages, and oligodendrocytes.

Globoid cell leukodystrophy (Krabbe disease) is a sphingolipidosis with an autosomal recessive inheritance pattern. It is caused by mutation of the GALC gene (14q31) which results in deficiency of the galactosylceramidase enzyme. Asymptomatic at birth, affected patients begin to develop symptoms within the first few months of life including irritability, stiffness, and delayed motor development. Accumulation of galactosylceramide in macrophages of the brain results in enlarged, multinucleated, globoid cells. White matter damage (leukodystrophy) occurs secondary to myelin degeneration and oligodendrocyte loss.

 

Pelizaeus-Merzbacher disease is an X-linked leukodystrophy caused by abnormalities of the proteolipid protein 1 (PLP1) gene (Xq22.2). Alteration of this gene results in hypomyelination and loss of oligodendrocytes with a characteristic sparing of the subcortical fibers. The peripheral nervous system is not affected.

 

Alexander disease is a leukodystrophy caused by a mutation of the GFAP gene (17q21). Microscopic changes include loss of myelin and marked formation of Rosenthal fibers, particularly in a perivascular and subpial distribution.

 

Wilson disease (hepatolenticular degeneration) is characterized by the accumulation of copper within the body. It is the result of mutation of the ATP7B gene which is involved in copper metabolism. With the accumulation of copper, patients develop cirrhosis, movement disorders, and psychiatric symptoms. Grossly, the brain may be discolored brown in the lenticular nucleus (putamen, globus pallidus).