X-linked adrenoleukodystrophy: Genes, mutations, and phenotypes

X-linked adrenoleukodystrophy (X-ALD) is a complex and perplexing neurodege nerative disorder. The metabolic abnormality, elevated levels of very long- chain fatty acids in tissues and plasma, and the biochemical defect, reduce d peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity, are ubiq uitous features of the disease; However, clinical manifestations are highly variable with regard to time of onset, site of initial pathology and rate of progression. In addition, the abnormal gene in X-ALD is not the gene for VLCS. Rather, it encodes a peroxisomal membrane protein with homology to t he ATP-binding cassette (ABC) transmembrane transporter superfamily of prot eins. The X-ALD protein (ALDP) is closely related to three other peroxisoma l membrane ABC proteins. In this report we summarize all known X-ALD mutati ons and establish the lack of an X-ALD genotype/phenotype correlation. We c ompare the evolutionary relationships among peroxisomal ABC proteins, demon strate that ALDP forms homodimers with itself and heterodimers with other p eroxisomal ABC proteins and present cDNA complementation studies suggesting that the peroxisomal ABC proteins have overlapping functions. We also esta blish that there are at least two peroxisomal VLCS activities, one that is ALDP dependent and one that is ALDP independent. Finally, we discuss variab le expression of the peroxisomal ABC proteins and ALDP independent VLCS in relation to the variable clinical presentations of X-ALD.