Defective metabolism of Leukotriene B 4 in the Sjögren–Larsson Syndrome

Abstract

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) B 4 is a pro-inflammatory mediator synthesized from arachidonic acid. LTB 4 is inactivated by microsomal ω-oxidation, successively yielding 20-OH-LTB 4, 20-CHO-LTB 4 and 20-COOH-LTB 4. Since FALDH is involved in LTB 4 degradation, we have analyzed LTB 4 and its metabolites in urine and cerebrospinal fluid as well as the degradation capacity for LTB 4 in fresh polymorphonuclear leukocytes (PMN) of SLS patients. The urinary concentrations of LTB 4, 20-OH-LTB 4 and 20-COOH-LTB 4 are below the detection limit in healthy controls. The urine of all SLS patients ( n=13) exhibited highly elevated concentrations of LTB 4 and 20-OH-LTB 4, while 20-COOH-LTB 4 was absent. Cerebrospinal fluid levels of LTB 4, 20-OH-LTB 4 and 20-COOH-LTB 4 were found to be normal ( n=7). PMN isolated from four patients were shown to be unable to convert 20-OH-LTB 4 to 20-COOH-LTB 4. Our findings provide unambiguous evidence for defective LTB 4 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.