Chapter 153. Disorders of Leukotriene Synthesis and Fatty Aldehyde Dehydrogenase

Leukotrienes are lipids derived from 20-carbon polyunsaturated fatty acids and are best known as mediators of inflammation. They are synthesized in many tissues, including the brain, and have a very short half-life in vivo. Two disorders are known in which biosynthesis is defective. Another disorder, Sjögren-Larsson syndrome, appears to be due to impaired leukotriene degradation.

A recessively inherited defect in biosynthesis of cysteine-containing leukotrienes has been demonstrated in two siblings with severe hypotonia, developmental retardation, microcephaly, and early death. Laboratory studies showed extremely low concentrations of several leukotrienes in plasma, urine, and cerebrospinal fluid and showed defective biosynthesis of the initial cysteinyl-leukotriene, LTC4. A postulated inherited defect in LTC4 synthase has not yet been proven by enzyme assay or by demonstrating mutations in the gene that encodes it. Another possible defect in leukotriene biosynthesis has been described in a 15-year-old male with mental retardation, mild motor retardation, deafness, and reduced excretion of LTE4, the major urine metabolite of leukotrienes. A possible defect in LTE4 biosynthesis has not been proved.1

Sjögren-Larsson Syndrome (SLS) is a recessively inherited neurocutaneous disorder caused by a defect in fatty aldehyde dehydrogenase (FALDH), which catalyzes the oxidation of fatty aldehydes to fatty acids. The condition is characterized by ichthyosis, mental retardation, and spastic diplegia, possibly because the substrates of FALDH are particularly prominent in the skin and brain. Pathogenesis of the disorder is complex and not well understood, but pruritus is probably due to accumulation of specific leukotrienes in the skin. Diagnosis is made by assay of FALDH in tissues, including leukocytes or cultured fibroblasts, or by molecular analysis of ALDH3A2, the gene that encodes FALDH and that is located on chromosome 17 (17p11.2).2