Clinical and Basic Investigations into Known and Suspected

多烯二酚是甲氧戊酸途径的长链类异戊二烯产物，在蛋白质和某些脂类糖基化的初始步骤中起作用。最近，发现了遗传性的苯二醇合成或利用障碍。患者出现不同的多器官症状，并表现出脂质和蛋白质糖基化缺陷。很少有患者被确认，而且对这些疾病的纵向自然病史知之甚少或一无所知。虽然许多患者都有糖基化不足的蛋白质，但尚未确定与疾病严重程度相关或可用于监测疾病进展的生物标记物。此外，目前还不存在针对异戊二烯类疾病的有效治疗方法。基于已知的苯二醇合成途径，很可能还有新的苯二醇代谢疾病有待发现。 我们建议通过系统地描述其临床特征并记录它们如何随时间变化来定义多巴酚代谢先天错误的自然病史。每年将进行全面的临床评估，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，以表征已知的DOLICHOL基因的分子缺陷，并利用整个外显子组测序寻找更多与DOLICHOL相关的新疾病基因。通过这种方式，我们将获得对这些罕见疾病的临床特征和自然历史的新见解。

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.