General aspects and neuropathology of X-linked adrenoleukodystrophy.

[adrenomyeloneuropathy]

X-adrenoleukodystrophy (X-ALD ) is a metabolic , peroxisomal disease affecting the nervous system , adrenal cortex and testis resulting from inactivating mutations in ABCD 1 gene which encodes a peroxisomal membrane half -adenosine triphosphate (ATP )-binding cassette transporter , ABCD 1 (or ALDP ), whose defect is associated with impaired peroxisomal beta -oxidation and accumulation of saturated very long -chain fatty acids (VLCFA ) in tissues and body fluids . Several phenotypes are recognized in male patients including cerebral ALD in childhood , adolescence or adulthood , adrenomyeloneuropathy (AMN ), Addison 's disease and , eventually , gonadal insufficiency . Female carriers might present with mild to severe myeloneuropathy that resembles AMN . There is a lack of phenotype-genotype correlations , as the same ABCD 1 gene mutation may be associated with different phenotypes in the same family , suggesting that genetic , epigenetic , environmental and stochastic factors are probably contributory to the development and course of the disease . Degenerative changes , like those seen in pure AMN without cerebral demyelination , are characterized by loss of axons and secondary myelin in the long tracts of the spinal cord , possibly related to the impaired lipid metabolism of VLCFAs and the associated alterations (ie , oxidative damage ). Similar lesions are encountered following inactivation of ABCD 1 in mice (ABCD 1 (-)). A different and more aggressive phenotype is secondary to cerebral demyelination , very often accompanied by inflammatory changes in the white matter of the brain and associated with activation of T lymphocytes , CD 1 presentation and increased levels of cytokines , gamma-interferon , interleukin (IL )-1 alpha , IL -2 and IL -6 , Granulocyte macrophage colony-stimulating factor (GM -CSF ), tumor necrosis factor -alpha , chemokines and chemokine receptors .

Diseases
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Diseases presenting "lack of phenotype-genotype correlations" symptom

adrenomyeloneuropathy

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