Sjögren–Larsson syndrome: Molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency

Abstract

Sjögren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase (FALDH), an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. Affected patients display ichthyosis, mental retardation and spastic diplegia. More than 70 mutations in ALDH3A2 have been discovered in SLS patients including amino acid substitutions, deletions, insertions and splicing errors. Most mutations are private, but several common mutations reflect founder effects, consanguinity or recurrent mutational events. FALDH oxidizes fatty aldehyde substrates arising from metabolism of fatty alcohols, leukotriene B4, ether glycerolipids and other potential sources such as sphingolipids. The pathogenesis of the cutaneous and neurologic symptoms is thought to result from abnormal lipid accumulation in the membranes of skin and brain; the formation of aldehyde Schiff base adducts with amine-containing lipids or proteins; or defective eicosanoid metabolism. Therapeutic approaches are being developed to target specific metabolic defects associated with FALDH deficiency or to correct the genetic defect by gene transfer.

Mouse aldehyde dehydrogenase ALDH3B2 is localized to lipid droplets via two C-terminal tryptophan residues and lipid modification

“…Hexadecenal is oxidized to hexadecenoic acid by ALDH3A2 and is further metabolized to glycerophospholipids [13]. ALDH3A2 is the causative gene of the neurocutaneous disorder Sjögren-Larsson syndrome [2], whose pathology is believed to be caused by the accumulation of lipid-derived aldehydes, including hexadecenal [12][13][14]. Oxidative stress generates free radicals that react with unsaturated fatty acids, and the resulting lipid hydroperoxides are degraded into several compounds, such as 4-HNE from n-6 polyunsaturated fatty acids [35].…”

“…The cytotoxicity of aldehyde molecules is evidenced by the fact that mutations in human ALDH genes can give rise to several inherited disorders, such as Sjögren-Larsson syndrome (ALDH3A2) [2], type II hyperprolinemia (ALDH4A1) [3], pyridoxine-dependent seizures (ALDH7A1) [4], γ-hydroxybutyric aciduria (ALDH5A1) [5], and methylmalonic aciduria (ALDH6A1) [6].…”

Spastic diplegia with nonperinatal asphyxia in pediatric population

“…18 SjogrenLarsson syndrome, one of the IEMs due to mutations in the ALDH3A2 gene coding fatty aldehyde dehydrogenase, causes ichthyosis, developmental delay and spastic diplegia. 19 Furthermore, cretinism due to maternal iodine deficiency has been reported to cause spastic diplegia in children. 20 To make a diagnosis of metabolic disorders, good history taking is essential because patients with metabolic disorders usually have no symptoms but develop encephalopathy under stressful conditions provoked by illness or high protein intake.…”

Novel and recurrent ALDH3A2 mutations in Italian patients with Sjögren–Larsson syndrome

“…FALDH is a microsomal enzyme that oxidizes mediumand long-chain aliphatic aldehydes derived from metabolism of fatty alcohol, phytanic acid, ether glycerolipids and leukotriene B4 (Rizzo 2007). Fatty alcohols are oxidized by a fatty alcohol:NAD + oxidoreductase enzyme complex consisting of two protein components, fatty alcohol dehydrogenase and FALDH, which sequentially metabolize fatty alcohol to fatty aldehyde and fatty acid, respectively (Ichihara et al 1986).…”

“…FALDH deficiency also leads to accumulation of leukotriene B4 (Willemsen et al 2001b) and aldehydemodified phosphatidylethanolamine (James and Zoeller 1997). Altered membrane lipid composition in skin and brain is thought to be responsible for the symptoms in SLS (Rizzo 2007).…”