Defining ichthyosis in Sjogren-Larsson syndrome for clinical trial preparedness

项目摘要 Sjön-Larsson综合征（SLS）是一种罕见的神经皮肤疾病，由ALDH 3A 2突变引起，与 脂肪醛脱氢酶（FATIGUE DEHYDROGENERATION，FATIGUE DH）活性不足。SLS的症状包括先天性鱼鳞病，痉挛性 双侧瘫痪智力残疾还有一种特殊的视网膜病β-DH缺乏导致脂肪醇的积累， 角质层中的醚甘油酯（烷基甘油）和胆固醇。SLS的患病率估计为 一比二十五万。 没有FDA批准的药物用于SLS或其他形式的鱼鳞病。尽管SLS的临床试验基于已知的 酶和生物化学缺陷才刚刚开始，评估治疗效果的皮肤 症状患有鱼鳞病严重程度的不精确测量，目前依赖于主观的临床 单独判断，缺乏有效的皮肤生物标志物。我们建议在未来的临床试验中解决这一弱点。 SLS试验通过应用创新方法客观测量鱼鳞病严重程度和表征新的 发现皮肤脂质异常 作为纵向研究的一部分，将从我们机构已经随访的患者中招募15名SLS受试者。 SLS的自然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 方法采用剪切波弹性成像，表征表皮水屏障功能异常，评分 使用经验证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 与角质层脂肪含量的烷基甘油和胆固醇有关。完成后，这些研究将 定义Sjör-Larsson综合征中鱼鳞病的结构和功能严重程度，并可能识别脂质 这些生物标志物对临床试验很重要。

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.