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adrenoleukodystrophies

Wednesday 29 March 2006

Definition: Adrenoleukodystrophy is a progressive disease with symptoms referable to myelin loss from the CNS and peripheral nerves as well as adrenal insufficiency. In general, forms with earlier onset have a more rapid course.

Types

- X-linked adrenoleukodystrophy (MIM.300100) (ABCD1 at Xq28)
- autosomal neonatal adrenoleukodystrophy (MIM.202370)

  • Locus 22q11
  • Locus Chr.1
  • Locus 12p13.3
  • Locus 7q21-q22
  • Locus 2p15

The X-linked form usually presents in the early school years with neurologic symptoms and adrenal insufficiency and is rapidly progressive and fatal. In individuals with later onset, the course is more protracted; when it develops in adults, it is usually a slowly progressive disorder with predominantly peripheral nerve involvement developing over a period of decades.

Rare, X-linked recessive adrenoleukodystrophy affects 1 in 120,000 males. It associates progressive demyelination of central and peripheral nervous system (dementia, blindness, quadriplegia) and adrenocortical insufficiency.

X-linked recessive adrenoleukodystrophy is associated with mutations in the ALD gene on chromosome Xq28, which encodes a member of the ATP-binding cassette transporter family of proteins. However, there is little correlation between clinical course and the underlying mutations.

The disease is characterized by the inability to properly catabolize very-long-chain fatty acids (VLCFA) within peroxisomes, with elevated levels of VLCFA in serum.

There is loss of myelin, with relative preservation of the subcortical U fibers, accompanied by gliosis and lymphocytic inflammation. Atrophy of the adrenal cortex is present, and VLCFA accumulation can be seen in remaining cells.

Mutations of adrenoleukodystrophy protein (ADLP) in peroxisomal membrane at Xq28 cause defective oxidation of long-chain fatty acids. Cholesterol esters and gangliosides accumulate in membranes of adrenal cortex, brain, other organs.

Heterozygous

Women may have a variant form of disease or no neurologic symptoms. The major pathologic differences between hemizygote and heterozygote are quantitative in nature. (3813829):

- striated adrenocortical cells without inflammation
- central nervous system demyelinative lesions

Diagnosis

- presence of hexacosanoate and other very long-chain saturated fatty acids in cultured skin fibroblasts.

Treatment

- dietary therapy (Lorenzo oil) may delay neurologic progression

Macrosocpy

- atrophic adrenal glands
- 1-2 g

Microscopy

- ballooning and striation of zona fasciculata and reticularis cells, often in nodules
- adrenal cells may have large cortical vacuoles and clefts (representing lipid dissolved during processing)
- adrenal medulla unchanged
- cerebral white matter exhibits demyelination, inflammation, gliosis and macrophages
- abnormalities of schwann cells in peripheral nerves
- abnormalities of Leydig cells in testis

Ultrastructuire

- proliferation of smooth endoplasmic reticulum
- trilaminar lamellar inclusions

Differential diagnosis

- autoimmune adrenalitis (lymphocytes and no balloon cells)

Videos

- Adrenoleukodystrophy by Washington Deceit

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References

- Chemke J, Livni N, Rosenmann E. Adrenoleukodystrophy: evidence for cytoplasmic inclusions in white blood cells. Pediatr Pathol. 1986;6(2-3):173-9. PMID: 3029738

- Applegarth DA, Dimmick JE. Adrenoleukodystrophy, cerebrohepatorenal syndrome (Zellweger syndrome), and peroxisomes. Pediatr Pathol. 1985;3(2-4):377-8. PMID: 4095031

- Powers JM, Moser HW, Moser AB, Schaumburg HH. Fetal adrenoleukodystrophy: the significance of pathologic lesions in adrenal gland and testis. Hum Pathol. 1982 Nov;13(11):1013-9. PMID: 6759362