title: X-linked adrenoleukodystrophy: genes, mutations, and phenotypes.
abstract: X-linked adrenoleukodystrophy (X-ALD) is a complex and perplexing neurodegenerative disorder. The metabolic abnormality, elevated levels of very long-chain fatty acids in tissues and plasma, and the biochemical defect, reduced peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity, are ubiquitous 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 the ATP-binding cassette (ABC) transmembrane transporter superfamily of proteins. The X-ALD protein (ALDP) is closely related to three other peroxisomal membrane ABC proteins. In this report we summarize all known X-ALD mutations and establish the lack of an X-ALD genotype/phenotype correlation. We compare the evolutionary relationships among peroxisomal ABC proteins, demonstrate that ALDP forms homodimers with itself and heterodimers with other peroxisomal ABC proteins and present cDNA complementation studies suggesting that the peroxisomal ABC proteins have overlapping functions. We also establish that there are at least two peroxisomal VLCS activities, one that is ALDP dependent and one that is ALDP independent. Finally, we discuss variable expression of the peroxisomal ABC proteins and ALDP independent VLCS in relation to the variable clinical presentations of X-ALD.
authors.affiliation: The Kennedy Krieger Institute and Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. smithk@welchlink.welch.jhu.edu
authors.forename: K D
authors.initials: KD
authors.lastname: Smith
authors.forename: S
authors.initials: S
authors.lastname: Kemp
authors.forename: L T
authors.initials: LT
authors.lastname: Braiterman
authors.forename: J F
authors.initials: JF
authors.lastname: Lu
authors.forename: H M
authors.initials: HM
authors.lastname: Wei
authors.forename: M
authors.initials: M
authors.lastname: Geraghty
authors.forename: G
authors.initials: G
authors.lastname: Stetten
authors.forename: J S
authors.initials: JS
authors.lastname: Bergin
authors.forename: J
authors.initials: J
authors.lastname: Pevsner
authors.forename: P A
authors.initials: PA
authors.lastname: Watkins
mesh_terms: D000326:Adrenoleukodystrophy / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D014960:X Chromosome / Q000235:genetics*