Molecular Basis of the Disease

X-ALD is a severe, often fatal disease that manifests in a progressive demyelination of the central nervous system, dysfunction of the adrenal cortex, and testicular dysfunction in hemizygous males. The most common form has an early onset that typically appears at 4 to 8 years of age and results in a progressive irreversible dementia and often death. Less severe presentations of the disorder include adreno-myeloneuropathy (AMN), which has a later age of onset, often adrenal insufficiency, and neurological complications that are limited to the spinal cord and peripheral nerves.26 Although the disease is inherited in an X-linked recessive manner, up to 20% of carrier females manifest late onset neurological symptoms similar to AMN. More than 93% of X-ALD patients inherit mutations from their mothers, while the remaining 7% carry de novo mutations. The primary biochemical defect is an impaired peroxisomal P-oxidation with the subsequent accumulation of very-long-chain fatty acids (VLCFAs),most notably C26, in the plasma and tissues. Therefore, X-ALD is not a disorder of peroxisomal biogen-esis,but rather a specific defect of peroxisomal function. The accumulation of VLCFAs and the accompanying inflammatory response are thought to mediate the severity of the disease phenotype. In the great majority of hemizygous males (99%) and approximately 85% of carrier females, the plasma concentration of VLCFAs is elevated, a measurement that can be used as a diagnostic marker for the disease.27

Defects in the peroxisomal membrane protein, ALDP, a member of the ATP-binding cassette family of molecular transporters, cause the severe juvenile form of X-ALD and its milder associated forms. The X-ALD gene, ABCD1, is located on Xq28, spans 19kb, contains 10 exons, and encodes a protein of 745 amino acids. The overall incidence of X-ALD and all variant forms is 1 in 15,000, making it the most common genetic determinant of peroxisomal disease. More than 400 different mutations have been found in the ABCD1 gene, with the vast majority being point mutations, although deletions and duplications also have been identified (http://www.x-ald.nl/). In addition, mutations in all 10 exons have been reported. No genotype-phenotype correlations are apparent, and wide phenotypic variation has been reported within families.

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