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 brain white matter and adrenal cortex, is the most common inherited peroxisomal disorder. The biochemical defect is localized to the level of lignoceroyl-CoA synthesis, a step in the peroxisomal beta-oxidation of very long chain fatty acids. The responsible gene encodes a peroxisomal integral membrane protein of as yet unknown function which is a member of the ATP-binding cassette transporter protein superfamily. The patient gene mutations are heterogeneously distributed over the functional protein domains with a tendency to clustering in the nucleotide-binding fold. The mechanisms by which these mutations cause a loss of protein function is unknown. Diagnosis of patients and carriers, including prenatal testing, is mainly based on the clinical picture, the demonstration 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 phenotypes commonly occur within the same kindred. Modifying genes and/or environmental factors may contribute to this phenomenon. At present, there is no proven therapy for the prevention or cure of the neurological disabilities. Several approaches are under investigation including diets, immunosuppression, bone marrow transplantation and gene therapy.