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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.
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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
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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
1. Mayatepek E. Leukotriene C
4 synthesis
deficiency: a member of a probably underdiagnosed new group of neurometabolic
diseases.
Eur J Pediatr. 2000;159:811.
[PubMed: 11079193]
2. Rizzo WB. Sjogren-Larsson syndrome: molecular genetics and
biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency.
Molec
Genet Metab. 2006;90:1.
[PubMed: 16996289]