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ALDH 3A 2基因突变引起，ALDH 3A 2基因编码脂肪醛脱氢酶（ALDHDH），导致异戊二烯醇氧化缺陷和脂质代谢异常。患者通常表现出鱼鳞病，智力残疾，痉挛，癫痫发作和一个独特的黄斑病变。虽然该病在50多年前就有描述，但对SLS的纵向自然史研究尚不存在，这种罕见疾病的临床谱尚未建立。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入组。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。将通过MRI/MRS、EEG、光学相干断层扫描、皮肤照片和神经精神检查记录神经系统、眼科、皮肤和神经精神变化。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。将临床和实验室数据相关联，以确定预测疾病严重程度和进展的有用生物标志物。将建立血液（血浆、红细胞）、尿液、皮肤活检和角质细胞培养物的SLS生物储存库，与STAIR和外部研究者共享。当这项研究完成后，我们希望有一个全面的知识的自然历史和临床变化的SLS。从这项研究中发现的生物标志物应该作为监测治疗试验的有效疾病指标。

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.