Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)395-406
Number of pages12
JournalExpert Opinion on Orphan Drugs
Volume4
Issue number4
DOIs
StatePublished - Apr 2 2016

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long-chain-aldehyde dehydrogenase
Aldehydes
Peroxisome Proliferator-Activated Receptors
Farnesol
Ichthyosis
Diet Therapy
Lipids
MAP Kinase Signaling System
Poisons
Expert Testimony
Rare Diseases
Intellectual Disability
Pharmaceutical Preparations
Genetic Therapy
Membrane Proteins
Therapeutics
Antioxidants
Phosphorylation
Alcohols
Clinical Trials

Keywords

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

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
  • Health Policy
  • Pharmacology (medical)

Cite this

Genetics and prospective therapeutic targets for Sjögren-Larsson Syndrome. / Rizzo, William B.

In: Expert Opinion on Orphan Drugs, Vol. 4, No. 4, 02.04.2016, p. 395-406.

Research output: Contribution to journalArticle

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