Defining ichthyosis in Sjogren-Larsson syndrome for clinical trial preparedness

项目总结 Sjögren-Larsson综合征(SLS)是一种罕见的神经皮肤病，由ALDH3A2基因突变引起，与 脂肪醛脱氢酶(FALDH)活性不足。系统性红斑狼疮的症状包括先天性鱼鳞病、痉挛 双瘫，智力残疾，和一种独特的视网膜病变。FALDH缺乏会导致脂肪醇的堆积， 角质层中的乙醚甘油脂(烷基甘油)和胆固醇。系统性红斑狼疮的患病率估计为 1：25万。 目前还没有FDA批准的治疗SLS或其他形式鱼鳞病的药物。尽管SLS的临床试验基于已知的 酶和生化缺陷才刚刚开始，评价对皮肤的治疗效果 症状对鱼鳞病严重程度的测量不准确，目前依赖于主观的临床。 仅凭判断，缺乏有效的皮肤生物标记物。我们建议在未来的临床中解决这一弱点。 应用创新方法客观测量鱼鳞病严重程度和新特征的SLS试验 在皮肤中发现了脂肪异常。 作为纵向调查的一部分，我们将从我们机构已经跟踪调查的人中招募15名SLS受试者 SLS的自然历史研究。我们将使用创新的高频超声波来定义皮肤厚度和弹性 方法应用剪切波弹性成像技术，对表皮水屏障功能异常进行评分。 使用有效的临床评分系统评估鱼鳞病的临床严重程度，并确定这些措施是否 与角质层脂肪含量、烷基甘油和胆固醇相关。完成后，这些研究将 明确Sjögren-Larsson综合征鱼鳞病的结构和功能严重程度，并潜在地识别脂质 生物标记物对临床试验将是重要的。

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.