Defining ichthyosis in Sjogren-Larsson syndrome for clinical trial preparedness

项目总结

PROJECT SUMMARY Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disease caused by mutations in ALDH3A2 and associated with deficient activity of fatty aldehyde dehydrogenase (FALDH). Symptoms of SLS include congenital ichthyosis, spastic diplegia, intellectual disability, and a distinctive retinopathy. FALDH deficiency results in accumulation of fatty alcohols, ether glycerolipids (alkylglycerols) and cholesterol in the stratum corneum. The prevalence of SLS is estimated to be 1:250,000. There are no FDA-approved drugs for SLS or other forms of ichthyosis. Although clinical trials in SLS based on the known enzymatic and biochemical defects are just now beginning, evaluation of treatment efficacy for the cutaneous symptoms suffers from an imprecise measure of ichthyosis severity, which currently relies on subjective clinical judgment alone, and lack of an effective cutaneous biomarker. We propose to address this weakness for future clinical trials of SLS by applying innovative methods for objectively measuring ichthyosis severity and characterizing newly discovered lipid abnormalities in the skin. A population of 15 SLS subjects will be recruited from those already followed at our institution as part of a longitudinal natural history study of SLS. We will define skin thickness and elasticity using innovative high frequency ultrasound methods with shear wave elastography, characterize functional abnormalities in the epidermal water barrier, score clinical severity of the ichthyosis using a validated clinical scoring system, and determine whether these measures correlate with stratum corneum lipid content of alkylglycerols and cholesterol. When completed, these studies will define the structural and functional severity of ichthyosis in Sjögren-Larsson syndrome and potentially identify lipid biomarkers that will be important for clinical trials.