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.

KEY WORDS:

• Aldehyde dehydrogenase
• aldehyde scavenging drugs
• fatty alcohol
• fatty aldehyde
• ichthyosis
• intellectual disability
• spasticity

Article highlights

• Sjögren–Larsson syndrome (SLS) is a rare genetic disease characterized by ichthyosis, intellectual disability, spasticity and a distinctive maculopathy.

• SLS is caused by mutations in ALDH3A2 that result in deficient activity of fatty aldehyde dehydrogenase (FALDH) and abnormal long-chain aldehyde metabolism.

• The pathogenic mechanisms are likely related to formation of fatty aldehyde adducts with lipids and proteins and/or accumulation of fatty alcohol and related lipids, which disrupt critical membranes, interfere with cell signaling and/or alter gene expression.

• Prospective therapeutic approaches include use of aldehyde trapping agents to block adduct formation (currently in phase 2 clinical trials), pharmacologically enhance residual FALDH activity, modulate cell-signaling pathways, restrict dietary intake of aldehyde-related lipids and decrease toxic aldehydes generated by oxidative stress.

• Gene therapy for SLS is a future goal that must address the need for multi-organ gene replacement or correction. This box summarizes the key points contained in the article.

Declaration of interest

WB Rizzo has received funding from Aldeyra Therapeutics for the study of NS2 in Sjogren-Larsson syndrome. Some of the research described in this work was funded in part by the Sterol and Isoprenoid Diseases Consortium (STAIR) (U54HD061939), which is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS). STAIR is funded through collaboration between NCATS and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.