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.