Defective metabolism of leukotriene B4 in the Sjögren-Larsson syndrome.
The Sjögren-Larsson Syndrome (SLS) is a neurocutaneous disorder, caused by deficient activity of the microsomal enzyme fatty aldehyde dehydrogenase (FALDH). FALDH catalyzes the oxidation of medium- and long-chain fatty aldehydes to their corresponding carboxylic acids. SLS is diagnosed by demonstrating the enzyme deficiency or by mutation analysis of the FALDH gene, while laboratory investigations of plasma, urine, and cerebrospinal fluid do not reveal any diagnostic abnormality. Leukotriene (LT) B4 is a pro-inflammatory mediator synthesized from arachidonic acid. LTB4 is inactivated by microsomal omega-oxidation, successively yielding 20-OH-LTB4, 20-CHO-LTB4 and 20-COOH-LTB4. Since FALDH is involved in LTB4 degradation, we have analyzed LTB4 and its metabolites in urine and cerebrospinal fluid as well as the degradation capacity for LTB4 in fresh polymorphonuclear leukocytes (PMN) of SLS patients. The urinary concentrations of LTB4, 20-OH-LTB4 and 20-COOH-LTB4 are below the detection limit in healthy controls. The urine of all SLS patients (n=13) exhibited highly elevated concentrations of LTB4 and 20-OH-LTB4, while 20-COOH-LTB4 was absent. Cerebrospinal fluid levels of LTB4, 20-OH-LTB4 and 20-COOH-LTB4 were found to be normal (n=7). PMN isolated from four patients were shown to be unable to convert 20-OH-LTB4 to 20-COOH-LTB4. Our findings provide unambiguous evidence for defective LTB4 degradation in SLS patients, and offer new and non-invasive diagnostic tools. Moreover, they open new pathophysiological considerations, with the prospect of rational treatment strategies.
Willemsen
M A
MA
Department of Pediatric Neurology, University Medical Center St. Radboud, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. m.willemsen@ckskg.azn.nl
Rotteveel
J J
JJ
de Jong
J G
JG
Wanders
R J
RJ
IJlst
L
L
Hoffmann
G F
GF
Mayatepek
E
E
D000293:Adolescent; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids; D007975:Leukotriene B4 / Q000031:analogs & derivatives / Q000378:metabolism*; D016111:Sjogren-Larsson Syndrome / Q000201:enzymology*
D006893:Hydroxyeicosatetraenoic Acids; D007975:Leukotriene B4; D016718:Arachidonic Acid; C031911:20-carboxyleukotriene B4; D000429:Alcohol Oxidoreductases; C058675:20-hydroxyleukotriene B4 dehydrogenase