Sjogren-Larsson Syndrome: a Longitudinal Study of Natural History

Sjogren-Larsson综合征（SLS）是一种罕见的遗传性疾病，由编码脂肪醛脱氢酶（FALDH）的ALDH3A2基因突变引起，导致异戊二醇氧化缺陷和脂质代谢异常。患者典型表现为鱼鳞病、智力残疾、痉挛、癫痫发作和独特的黄斑病变。虽然这种疾病早在50多年前就已被描述，但SLS的纵向自然史研究尚不存在，这种罕见疾病的临床谱系尚未建立。该病的发病机制尚不清楚，也没有特异性的基于发病机制的治疗方法。此外，与疾病严重程度或进展相关的生物标志物尚未建立。我们将对SLS进行纵向自然历史研究，以确定临床表型的长期变化，并寻找与症状严重程度和临床疾病相关的生物标志物。所有年龄段的受试者都将被招募。患者将接受详细的临床检查，记录他们的神经、皮肤和认知障碍。神经、眼科、皮肤和神经精神的变化将通过MRI/MRS、脑电图、光学相干断层扫描、皮肤照片和神经精神测试来记录。将使用脂质组学、蛋白质组学和基因表达方法研究血液、尿液、皮肤和皮肤鳞片的潜在生物标志物。临床和实验室数据将相互关联，以确定预测疾病严重程度和进展的有用生物标志物。将建立一个SLS生物库，包括血液（血浆、红细胞）、尿液、皮肤活检和角质细胞培养，以便与STAIR和外部调查人员共享。当这项研究完成后，我们期望对SLS的自然史和临床变异有一个全面的了解。从这项研究中发现的生物标记物应该作为疾病监测治疗试验的有效措施。

Project 2 Sjogren-Larsson syndrome (SLS) is a rare genetic disease caused by mutations in ALDH3A2 that encodes fatty aldehyde dehydrogenase (FALDH) and results in defective isoprenol oxidation and abnormal lipid metabolism. Patients typically exhibit ichthyosis, intellectual disability, spasticity, seizures and a distinctive maculopathy. Although the disease was described more than 50 years ago, longitudinal natural history studies of SLS are non-existent and the clinical spectrum of this rare disease is not yet established. The pathogenic mechanisms of the disease remain unclear and no specific pathogenesis-based therapy exists. Moreover, biomarkers that correlate with disease severity or progression have not been established. We will conduct a longitudinal natural history study of SLS to define long term changes in clinical phenotype and search for biomarkers that correlate with symptom severity and clinical disease. Subjects of all ages will be enrolled. Patients will receive detailed clinical exams documenting their neurologic, dermatologic and cognitive disabilities. Neurologic, ophthalmologic, dermatologic, and neuropsychiatric changes will be documented with MRI/MRS, EEG, optical coherence tomography, cutaneous photographs and neuropsychiatric testing. Blood, urine, skin and cutaneous scales will be investigated for potential biomarkers using lipidomics, proteomics and gene expression methods. Clinical and laboratory data will be correlated to identify useful biomarkers that predict disease severity and progression. A SLS Biorepository of blood (plasma, erythrocytes), urine, skin biopsies and keratinocyte cultures will be established for sharing with STAIR and outside investigators. When this study is completed, we expect to have a thorough knowledge of the natural history and clinical variation of SLS. The biomarkers that will be discovered from this research should serve as validated measures of disease for monitoring therapeutic trials.