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Toward a rational therapy for X-linked adrenoleukodystrophy
X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited disorder of the central nervous system white matter. It is characterized by a striking and unpredictable variation in phenotypic expression, ranging from a rapidly progressive and fatal cerebral demyelinating disease in childhood, to the milder slowly progressive form in adulthood, and variants without neurological involvement. Currently, treatment options are very limited and are mostly symptomatic.
X-ALD is caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter ALDP. A defect in ALDP impairs peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) resulting in an accumulation of VLCFA in all tissues.
How a defect in ALDP and elevated VLCFA levels eventually result in the onset of disease and loss of myelin remains largely unresolved.
The major objective of our research is to resolve the role of VLCFA metabolism in the pathogenesis of X-ALD and use this knowledge for the development of a rationally based therapy for X-ALD.