Phenotypic Variability Among Adult Siblings With Sjögren-Larsson Syndrome

Department of Ophthalmology, Hebrew University of Jerusalem, Yerushalayim, Jerusalem, Israel
JAMA Neurology (Impact Factor: 7.42). 02/2006; 63(2):278-80. DOI: 10.1001/archneur.63.2.278
Source: PubMed


Sjögren-Larsson syndrome (SLS) is an early childhood-onset disorder with ichthyosis, mental retardation, spastic paraparesis, macular dystrophy, and leukoencephalopathy caused by the deficiency of fatty aldehyde dehydrogenase due to mutations in the ALDH3A2 gene (the gene that encodes microsomal fatty aldehyde dehydrogenase). Cerebral proton magnetic resonance spectroscopy in those with SLS demonstrates an abnormal white matter peak at 1.3 ppm, consistent with long-chain fatty alcohol accumulation.
To define the clinical course and proton magnetic resonance spectroscopic findings of SLS in adults.
Case series in a tertiary care center.
Six siblings of a consanguineous Arab family with early childhood-onset SLS who carry the 682C-->T mutation in the ALDH3A2 gene were reinvestigated in adulthood.
The 6 affected siblings ranged in age from 16 to 36 years. All exhibited the typical clinical and imaging manifestations of SLS, but their severity markedly varied. Neurological involvement was apparently nonprogressive, and its severity showed no correlation with age. Cerebral proton magnetic resonance spectroscopy showed a lipid peak at 1.3 ppm, with decreasing intensity in the older siblings.
These observations document significant clinical variability and the nonprogressive neurological course of SLS in adult siblings with the same ALDH3A2 genotype, and demonstrate possible correlation of proton magnetic resonance spectroscopic changes with age, suggesting unknown pathogenic mechanisms to compensate for the responsible biochemical defect in this disease.

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    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.
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