| Research theme | X-linked adrenoleukodystrophy |
|---|---|
| Principal Investigator | Dr. Stephan Kemp |
| Group members | Martin Schackmann, MSc Catherine van Engen, MD Marc Engelen, MD Rob Ofman, BSc Inge Dijkstra, BSc |
Mutations in the ABCD1 gene, encoding the peroxisomal ABC transporter ALDP, result in X-linked adrenoleukodystrophy (X-ALD) an inherited metabolic storage disorder. A defect in ALDP impairs peroxisomal ß-oxidation and leads to an accumulation of very long-chain fatty acids (VLCFA; > C22:0) in tissues of the body, especially brain and adrenal glands. X-ALD is the most common peroxisomal disorder with a birth incidence of 1:17.000. X-ALD is characterized clinically by a striking and unpredictable variation in phenotypic expression, ranging from the rapidly progressive childhood cerebral form (CCALD) to the more slowly progressive adult form adrenomyeloneuropathy (AMN) and variants without neurological involvement (“Addison-only” phenotype). In spite of identical mutations, patients can have markedly divergent neurological and neuropathologic characteristics. Currently, treatment options are very limited and are mostly symptomatic.
My research group performs true translational research on X-ALD by combining fundamental research with clinical research and clinical trials. The main focus of our research is on: 1) resolution of the role of VLCFA in the pathophysiology of X-ALD, 2) investigation of the therapeutic potential of inhibition of VLCFA synthesis 3), exploration of VLCFA omega-oxidation as a rescue pathway for X-ALD, and 4) identification of genetic markers that allows prediction of the phenotype development in X-ALD patients, or even in newborns.
Key publications
Kemp S, Theodoulou FL, Wanders RJ (2011) Mammalian peroxisomal ABC transporters. British Journal of Pharmacology: in press.
Ofman R, Dijkstra IME, van Roermund CWT, Burger N, Turkenburg M, van Cruchten A, van Engen CE, Wanders RJA and Kemp S (2010) The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy. EMBO Molecular Medicine 2(3): 90-97.
Engelen M, Ofman R, Dijkgraaf MGW, Hijzen M, v.d. Wardt LA, van Geel BM, de Visser M, Wanders RJA, Poll-The BT, Kemp S (2010) Lovastatin in X-Linked Adrenoleukodystrophy. New England Journal of Medicine 362(3): 276-277.
Sanders RJ, Ofman R, Dacremont G, Wanders RJA, Kemp S (2008) Characterization of the human ?-oxidation pathway for ?-hydroxy-very long-chain fatty acids. FASEB Journal. 22(6):2064-71.
Kemp S and Wanders RJ (2007) X-linked Adrenoleukodystrophy: very long-chain fatty acid metabolism, half ABC-transporters and the complicated route to treatment. Molecular Genetics Metabolism 90(3): 268-276.