X-linked Adrenoleukodystrophy

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Background    Neuroimaging    Gross Pathology    Histopathology & Immunohistochemistry Differential Diagnosis    Reference

BACKGROUND AND CLINICAL INFORMATION: Head  

Summary: X-linked adrenoleukodystrophy is a peroxisomal disease with combined involvement of the CNS and the adrenal glands. Progressive childhood onset is the most common presentation but clinical presentation is quite variable. Pathologically, X-ALD is characterized by lipid accumulation (birefrigent striations, also seen in other peroxisomal diseases) in the adrenal gland and testicular interstitial glands and inflammatory "three-zone" demyelinating lesions in the brain.

Clinical features: Over half of the patients present with the childhood form, about 25% have a late-onset presentation with adrenomyeloneuropathy, and 10% have isolated Addison disease.

Childhood onset type: Usually between 4 and 8 years of age, with progressive disturbances of gait and subtle cognitive decline. Only about 10% of the caes will develop features of adrenal cortical insufficiency. Symptoms of Addison's disease commonly appear before the neurologic symptoms, but may follow mental deterioration. Skin pigmentation is very uncommon. Acute onset with focal seizures may also occur. Spasticitiy, pseudobulbar symptoms, and dementia eventually develop. Cortical disturbances of vision and hearing are highly suggestive but are seldom observed. The rate of deterioration is extremely variable. Death usually sets in after a few months to a few years.

• Biochemistry: The ability to form coenzyme A derivatives of very long chain fatty acids (chain length over 22 carbon) is reduced. This lead to wide spread accumulation of very long chain fatty acid.

• Laboratory findings: very-long-chain fatty acids (VLCFAs) are regularly elevated and a C26:C22 ratio of 1.6 ± 0.84 in plasma and of 0.42 ± 0.15 in fibroblasts is characteristic. Heterozygotes also have increased C20:C23 ratios.

• Prenatal diagnosis: By analysis of VLCFAs in amniocytes and chorionic cells.

Molecular pathology: the ALD gene is located on chromsome Xq28 that encodes an ATP-binding cassette transpoter. It is 21 - 26 kB in length and generate a mRNA of 3.7 - 4.3 Kb that yield a protein of 745-750 amino acids (ALD protein).

• Mutations: A large number of mutations have been found, about half (54%)of them are missense mutations, half of the remaining half (25%) are frameshift mutation, the rest are nonsense (10%) and large deletions (7%). A mutation hotspot is identified on exon 5.

• ALD-protein: ALD gene expression is highest in adrenal glands, intermediate in brain, and almost undectable in liver. ALDP is highly expressed in microglia, astrocytes, and endothelial cells; oligodendrocytes have little to none.

NEUROIMAGING: Head  

Abnormal changes are seen more often in the parietal-occipital white matter. Small areas of hyperintensity are seen in the internal capsule. Lesions are usually symmetrical. MRI is sensitive enough to reveal lesions in asymptomatic patients.

GROSS PATHOLOGY: Head  

CNS:

• Lesions have a caudorostral progression. The white matter is gray and firm. The occipital, parietal, the temporal lobes are more affected with the frontal lobe less severely affected. The lesions are bilateral and symmetrical, and frequently span across the splenium of corpus callosum.

• Severe demyelination is also seen in the optic nerve.

Adrenal glands: The adrenal glands are usually small and atrophic.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

Adrenal glands: Histologically, the zona glomerulosa is preserved but the cells in zona fasiculata and reticulata are enlarged, secondary to the accumulation of cytoplasmic birefringent striation.

• 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.

Testis: SImilar laminar lipid lamellae are also seen in the interstial cells of the testis, as well as schwann cells and hepatocytes.

Brain: The cortical architecture appears normal. In the white matter, there is prominent demyelination with the subcortical U-fibers relatively preserved.

• Three zone demyelinating lesions: The demyelinating lesions appear to have a central gliotic scar surrounded by a mantale of demyelinating lesions with abundant sudanophilic macrophages, axons in various stages of demyelination, and substantial perivascular chronic inflammatory cell infiltration. The outer zone is characterized by active myelin break down with some sudanophilic macrophages but no inflammatory changes. The inflammatory changes appear to be reactive process to the breakdown of myelin. Such inflammatory response is not seen in neonatal adrenoleukodystrophy (NALD).

Electron microscopy: Peroxisome structure is normal.

DIFFERENTIAL DIAGNOSIS: Head  

Neonatal adrenoleukodystrophy has fundamental difference from X-ALD. Neonatal adrenoleukodystrophy is transmitted in an autosomal recessvie fashion and is resulted from loss or deficiency of all peroxisomal b-oxidation enzymes. Hepatic peroxisomes are absent or greatly diminished in neonatal adrenoleukodystrophy while peroxisomes are morphologically normal in X-ALD. The capacity to synthesize palsmalogens and oxidize phytanic acid is impaired and the plasma levels of pipecolic acid and bile intermediates are increased. None of these abnormal biochemical features are seen in X-ALD. 

Powers J et al., JNEN 2000 59:89.

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