Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome

Abstract

Introduction Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disease characterized by ichthyosis, spasticity, intellectual disability and a distinctive retinopathy. It is caused by inactivating mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase (FALDH) and results in abnormal metabolism of long-chain aliphatic aldehydes and alcohols. The potential disease mechanisms leading to symptoms include 1) accumulation of toxic fatty aldehydes that form covalent adducts with lipids and membrane proteins; 2) physical disruption of multi-lamellar membranes in skin and brain; 3) abnormal activation of the JNK cell signaling pathway; and 4) defective farnesol metabolism resulting in abnormal PPAR-α dependent gene expression. Currently, no effective pathogenesis-based therapy is available. Areas Covered The clinical, pathologic and genetic features of SLS are summarized. The biochemical abnormalities caused by deficient activity of FALDH are reviewed in the context of proposed pathogenic mechanisms and potential therapeutic interventions. Expert Opinion The most promising pharmacologic approach to SLS involves blocking the formation of potentially harmful fatty aldehyde adducts using aldehyde scavenging drugs, currently in phase 2 clinical trials. Other approaches needing further investigation include: 1) ALDH-specific activator drugs and PPAR-α agonists to increase mutant FALDH activity; 2) inhibitors of the JNK phosphorylation cascade; 3) antioxidants to decrease aldehyde load; 4) dietary lipid modification; and 5) gene therapy.

Genotype and phenotype variability in Sjögren-Larsson syndrome

“…Therapeutic options for SLS are currently limited to symptomatic treatment of cutaneous and neurologic manifestations (Rizzo, ). Oral retinoids and various topical treatments (e.g., urea containing creams) are used for skin manifestations (Gånemo, Jagell, & Vahlquist, ).…”

“…Seizures are controlled with antiepileptics (Gånemo et al., ). Novel innovative and prospective therapeutic approaches for SLS are currently under consideration and will potentially help to ease the burden of the severe symptoms of affected patients (Rizzo, ).…”

Clinical, biochemical, and genetic aspects of Sjögren‐Larsson syndrome

“…The major transcript of 10 exons encodes a protein of 485 amino acids located on endoplasmic reticulum, while the minor transcript (<10%) with an extra codon 9 (exon 9 0 ) encodes a variant isoform (FALDHυ) of 508 amino acids in peroxisomes. 21 The pathogenesis of SLS involves mutation of FALDH, a microsomal, nicotinamide-adenine-dinucleotide-dependent enzyme necessary for oxidation of long-chain aliphatic aldehydes between 6 and 24 carbons in length to fatty acids. 21 FALDH is a membrane-bound homo-oligomeric enzyme consisting of a cofactor-binding domain, a catalytic domain, and a carboxy-terminal (C-terminal) transmembrane domain for oligomerization.…”

“…21 The pathogenesis of SLS involves mutation of FALDH, a microsomal, nicotinamide-adenine-dinucleotide-dependent enzyme necessary for oxidation of long-chain aliphatic aldehydes between 6 and 24 carbons in length to fatty acids. 21 FALDH is a membrane-bound homo-oligomeric enzyme consisting of a cofactor-binding domain, a catalytic domain, and a carboxy-terminal (C-terminal) transmembrane domain for oligomerization. 22 As a part of the fatty alcohol: NAD + oxidoreductase (FAO) enzyme complex, FALDH interacts with fatty alcohol dehydrogenase to oxidize aldehydes.…”

“…4,9 However, as the severity of ichthyosis and neurologic symptoms are often not correlated, pathomechanisms may vary in individual tissues. 21 FALDH is vital to the degradation of various lipids: sphingosine-1-phosphate, ether-linked lipids; plasmalogens and alkylglycerols such as platelet-activating factor, and dietary lipids ( Figure 2). Degradation of hexadecenal, downstream of sphingosine-1-phosphate, is impaired when FALDH is deficient 26 : hexadecenal initiates Jun N-terminal kinase pathway that mediates cytoskeletal changes and apoptosis and that is suggested as the pathologic signaling pathway of SLS.…”