CLINICAL AND GENETIC-ASPECTS OF X-LINKED ADRENOLEUKODYSTROPHY

X-linked adrenoleukodystrophy (ALD), a leukodystrophy characterized by abnormal accumulation of saturated very long chain fatty acids in bra in white matter and adrenal cortex, is the most common inherited perox isomal disorder. The biochemical defect is localized to the level of l ignoceroyl-CoA synthesis, a step in the peroxisomal beta-oxidation of very long chain fatty acids. The responsible gene encodes a peroxisoma l integral membrane protein of as yet unknown function which is a memb er of the ATP-binding cassette transporter protein superfamily. The pa tient gene mutations are heterogeneously distributed over the function al protein domains with a tendency to clustering in the nucleotide-bin ding fold. The mechanisms by which these mutations cause a loss of pro tein function is unknown. Diagnosis of patients and carriers, includin g prenatal testing, is mainly based on the clinical picture, the demon stration of increased levels of saturated very long chain fatty acids in tissues and body fluids as well as on DNA mutation analyses. There are at least six distinct clinical phenotypes ranging from the severe childhood cerebral form to asymptomatic persons. The various phenotype s commonly occur within the same kindred. Modifying genes and/or envir onmental factors may contribute to this phenomenon. At present, there is no proven therapy for the prevention or cure of the neurological di sabilities. Several approaches are under investigation including diets , immunosuppression, bone marrow transplantation and gene therapy.