Toward a rational therapy for X-linked adrenoleukodystrophy
07 / 2007 - unknown
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. No therapy is available for X-ALD. All X-ALD patients have a mutation in the X-ALD gene that encodes a peroxisomal ABC half-transporter named ALDP. Mutations in ALDP result in deficient peroxisomal beta-oxidation and elevated levels of very long-chain fatty acids (VLCFA). How mutations in ALDP and elevated VLCFA levels eventually result in the onset of disease and loss of myelin remains largely unresolved. In addition, there is also no marker available that allows the prediction of the clinical course of a patient: neither X-ALD gene mutations nor plasma VLCFA levels have a predictive value. This indicates the existence of at least one other modifier gene involved in the development of the different X-ALD phenotypes. Our recent data have brought new insight into the biochemistry of X-ALD: deficient peroxisomal VLCFA beta-oxidation results in increased cytosolic VLCFA levels which are subsequently substrate for further elongation to even longer fatty acids. We also identified ELOVL1 as the pivotal enzyme responsible for both the synthesis of VLCFA and the subsequent further elongation of VLCFA.These findings have generated new perspectives with respect to the development of therapy and our understanding of the pathogenesis of X-ALD. Importantly, because of its function ELOVL1 is a primary modifier gene candidate. This grant application s major objectives are to resolve the role of VLCFA, ALDP and ELOVL1 in the pathogenesis and phenotype development of X-ALD and to use this knowledge for the development of a rationally based therapy for X-ALD.
Adrenoleukodystrofie (ALD), bekend van de film 'Lorenzo's oil', is een ernstige hersenziekte die veroorzaakt wordt door een verstoorde vetzuurhuishouding. De onderzoekers willen de ontstaanswijze van de ziekte ophelderen met als uiteindelijk doel deze kennis te gebruiken voor de ontwikkeling van een therapie.