Clinical and Basic Investigations into Known and Suspected

Dolichol是甲羟戊酸途径的长链类异戊二烯产物，其在蛋白质和某些脂质的糖基化的初始步骤中起作用。最近，已经发现了多萜醇合成或利用的遗传性疾病。患者表现出可变的多器官症状，并表现出脂质和蛋白质糖基化缺陷。很少有患者被确定，很少或根本不知道这些疾病的纵向自然史。尽管许多患者具有糖基化不足的蛋白质，但尚未鉴定出与疾病严重程度相关或可用于监测疾病进展的生物标志物。此外，还不存在对类异戊二烯疾病的有效疗法。基于已知的多萜醇合成途径，很可能新的多萜醇代谢疾病正在等待被识别。 我们建议通过系统地描述其临床特征并记录其如何随时间变化来定义多萜醇代谢先天性缺陷的自然史。每年将进行全面的临床评价，以确定症状的频率和变异性。我们将寻找与疾病严重程度和进展相关的最有用的生物标志物。对于那些缺乏DNA诊断的患者，我们将进行突变分析，以表征已知多萜醇基因中的分子缺陷，并使用全外显子组测序寻找其他新的多萜醇相关疾病基因。通过这种方式，我们将对这些罕见疾病的临床特征和自然史有新的认识。

Dolichols are long-chain isoprenoid products of the mevalonate pathway that act in the initial steps of glycosylation of proteins and certain lipids. Recently, inherited disorders of dolichol synthesis or utilization have been discovered. Patients present with variable multiorgan symptoms and exhibit defective lipid and protein glycosylation. Few patients have been identified and little or nothing is known about the longitudinal natural history these diseases. Although many patients have underglycosylated proteins, a biomarker that correlates with disease severity or can be used for monitoring disease progression has not been identified. Further, effective therapy for the isoprenoid diseases does not yet exist. Based on the known dolichol synthesis pathway, it is likely that new diseases of dolichol metabolism are waiting to be identified. We propose to define the natural history of inborn errors of dolichol metabolism by systematically characterizing their clinical features and documenting how they change over time. Comprehensive clinical evaluations will be performed every year to determine the frequency and variability of symptoms. We will search for the most useful biomarkers that correlate with disease severity and progression. For those patients lacking a DNA diagnosis, we will perform mutation analysis to characterize the molecular defects in the known dolichol genes and search for additional new dolichol-related disease genes using whole exome sequencing. In this fashion, we will achieve new insight into the clinical features and natural history of these rare diseases.