Chapter 98

## Abstract

Abstract

1. Sjögren-Larsson syndrome (SLS; MIM 270200) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, and spastic diplegia or tetraplegia. The disorder is caused by mutations in the gene for fatty aldehyde dehydrogenase (FALDH) that result in deficient enzyme activity and impaired oxidation of long-chain aliphatic aldehydes derived from fatty alcohol metabolism.

2. The clinical features of SLS become evident at birth or within the first 2 years of life. Most patients show generalized ichthyosis, mild to moderate mental retardation, and spastic diplegia that often prevents or impedes walking. The presence of glistening white dots on the perifoveal region of the retina is pathognomonic for SLS, but only one-third of patients exhibit this sign. Brain neuroimaging reveals white matter disease in most patients, and seizures are frequently seen. Because other diseases share many of its clinical features, the phenotype of SLS is not sufficiently distinct to permit unambiguous clinical diagnosis without biochemical confirmation.

3. Pedigree analyses indicate that SLS is inherited as an autosomal recessive trait, with males and females equally affected. The prevalence of SLS in Sweden, where the largest group of patients has been identified, is 0.4 per 100,000. The disease is seen worldwide, but the incidence is unknown.

4. Pathologic changes in the skin of SLS patients include hyperkeratosis, papillomatosis, acanthosis, and a mildly thickened granular layer. Electron microscopy of the skin reveals electron-lucent clefts and membranous inclusions in the stratum corneum and deeper layers. The major pathologic change in the brain involves loss of myelin.

5. Long-chain aliphatic aldehydes arise from metabolism of several lipids, including fatty alcohol, ether glycerolipids, sphingolipids, and phytanic acid, a dietary branched chain fatty acid. Of these potential lipid substrates, FALDH has been implicated in the oxidation of aldehydes derived from fatty alcohol and phytanic acid. It remains to be determined whether this enzyme is necessary for oxidation of aldehydes derived from ether glycerolipids and sphingolipids, which are prominent in the brain and skin. Aldehyde-generating lipids are present in the diet, but their contribution to the total body substrate pool is not defined.

6. FALDH is a microsomal enzyme that catalyzes the NAD-dependent oxidation of straight- and branched chain aliphatic aldehydes to their corresponding fatty acids. Fatty aldehyde substrates range from 6 to 24-carbons long. The catalytic mechanism involves formation of a covalently bound intermediate consisting of the aldehyde in a thioester linkage with an active site cysteine residue. FALDH is widely expressed in tissues. The active enzyme is probably a homodimer of identical 54-kDa subunits and shows amino acid sequence similarity to several other human aldehyde dehydrogenase isozymes. The 35 C-terminal amino acids of FALDH, missing from related isozymes, are necessary for targeting and anchoring the enzyme to the microsomal membrane.

7. The primary biochemical defect in SLS is impaired fatty aldehyde oxidation due to deficient FALDH activity. Owing to FALDH's involvement as a component of fatty alcohol:NAD oxidoreductase (FAO), its deficiency is associated with impaired oxidation of fatty alcohol, which results in fatty alcohol accumulation in plasma. A secondary effect of the FALDH defect is a reduction in certain serum polyunsaturated fatty acids in SLS patients.

8. The FALDH gene has been mapped to chromosome 17p11.2 and consists of 11 exons. Northern blot analysis shows three transcripts that vary in length due to differences in polyadenylation sites. In addition, splicing of the gene at alternative sites results in two transcripts that encode proteins differing in the C-terminal region.

9. A variety of mutations in the FALDH gene cause SLS. Two common mutations in European patients account for about one-half of the mutant alleles in that region of the world.

10. The pathogenesis of SLS is hypothesized to arise from accumulation of fatty aldehydes, which form covalent adducts with phosphatidylethanolamine and membrane proteins. The pathogenic effects of fatty alcohol accumulation and polyunsaturated fatty acid deficiency are unclear. Altered lipid composition of multilamellar membranes in the stratum corneum may disrupt the epidermal water barrier, leading to ichthyosis. Lipid alterations in myelin membranes are thought to be responsible for the white matter disease.

11. The diagnosis of SLS is readily made by demonstrating deficiency of FALDH or FAO activity in cultured skin fibroblasts, leukocytes, and other tissues. SLS heterozygotes tend to show a partial reduction in enzyme activity. SLS can now be diagnosed by mutation analysis in targeted populations or select kindreds. Prenatal diagnosis may be performed using enzymatic and DNA-based methods.

12. Therapy for SLS is largely symptomatic. Ichthyosis improves with topical keratolytic agents or systemic retinoids, and seizures, if present, respond to anti-convulsants. A fat-modified diet with supplemental medium-chain fatty acids has been used in several patients, with inconsistent results.

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