Lysosomal Disease Network

溶酶体疾病（LD）是一组约70种遗传性代谢疾病， 溶酶体功能缺陷;通常缺乏脂质代谢所需的单一酶， 糖蛋白或粘多糖。总的来说，LD并不特别罕见;估计表明， 大约1：5，000的新生儿将受到一种确定的LD的影响。然而，每种疾病 发生的频率要低得多。假设每100万活产婴儿中有180人将受到影响， LD，外推发生率范围为戈谢氏25/100万例新生儿至GM 1 - 7/100万例新生儿。 神经节苷脂沉积症;其他LD更罕见。大多数LD是单基因疾病，由一个突变引起， 单基因，遵循常染色体隐性遗传模式，尽管少数是X连锁隐性遗传。 虽然每个LD都是由一个独特的基因突变引起的，但在生化水平上，它们有一个共同的 特征-不能从溶酶体中清除代谢底物。呈现的症状差异很大 在这些疾病中，并根据发病年龄和严重程度进行修改（大多数LD表现为严重或 减毒表型）;除严重或减毒分类外，更特异的基因型/表型 相关性不可行。到目前为止，大约有十几个LD有治疗选择，但除了 MPS I已被证明适合干细胞移植，LD药物疗法不是特别有效 在那些有神经功能障碍的情况下而新的治疗方法，无论是下一代药物治疗， 基因治疗或其他基因编辑技术对于改善LD患者的预后至关重要， 早期发现对于LD患者希望正常生活至关重要。在过去的三十年里， 溶酶体疾病已经成为一些最具创新性的治疗方式的试验床。过去9 在NIH多年的资助下，LDN加速了该领域的知识获取--NCBI引用了95篇 出版物，并进一步发展的治疗方案。在接下来的五年里， LDN的主题目标是：临床试验准备，新生儿筛查，长期结果和全球 到达。我们将通过5项纵向研究的临床研究推进这些目标， 通过（a）庞贝氏症中的CRIM状态和免疫耐受诱导，（B） 法布里病的心脏和肾脏病理学，（c）多系统调查（心脏，发育，骨骼， 粘多糖症的QOL），以及（d）MRI和生物标志物的发展作为粘多糖症的结局指标 神经节苷脂沉积第五个项目是一项调查研究，旨在对奥德赛个人经历的 在达到正确的诊断和治疗的有效性，使个人与溶酶体 疾病（专门治疗MPS），过独立的生活。每个参加LDN项目的参与者 预计将完成调查研究。生物统计学分析确保了每一个相关的统计模型 项目

The lysosomal disorders (LD) are a group of approximately 70 inherited metabolic conditions resulting from defects in lysosomal function; usually deficiency of a single enzyme required for the metabolism of lipids, glycoproteins, or mucopolysaccharides. Collectively, LD are not especially rare; estimates suggest that approximately 1:5,000 newborns will be affected with one identified LD. Individually however, each disorder occurs with a much lower frequency. Assuming that 180 individuals per 1 million live births will be affected with an LD, extrapolation incidences range from Gaucher at 25 per 1 million births to 7 per 1 million births for GM1- gangliosidosis; other LD are much rarer still. Most LD are monogenetic disorders caused by a mutation in a single gene and follow an autosomal recessive inheritance pattern, although a few are X-linked recessive. Although each LD results from a unique gene mutation, at the biochemical level they share a common characteristic—the inability to clear metabolic substrate from the lysosome. Presenting symptoms vary widely among the disorders and are modified by age of onset and severity (most LD present as either a severe or attenuated phenotype); beyond categorization as severe or attenuated, a more specific genotype/phenotype correlation has not been feasible. To date, about a dozen or so LD have therapeutic options, but apart from MPS I, which has been shown amenable to stem cell transplant, LD drug therapies are not particularly effective in those conditions with neurologic dysfunction. And while new treatments, be it next generation drug therapy, gene therapy, or other gene editing techniques, are essential to improve outcomes for those affected with LD, early detection is critical in order for a person with an LD to hope for a normal life. In the past three decades, lysosomal diseases have been a test bed for some of the most innovative therapeutic modalities. In the past 9 years of NIH funding, the LDN has accelerated knowledge acquisition in the field—with 95 NCBI cited publications—and furthered the development of therapeutic options. For the next 5 years, the overarching thematic goals of the LDN are: clinical trial readiness, newborn screening, long-term outcomes, and global reach. We will advance these goals through clinical investigation via 5 longitudinal studies focused on elucidation of disease pathology by (a) CRIM status and immune tolerance induction in Pompe disease, (b) cardiac and kidney pathology in Fabry disease, (c) multi-system survey (cardiac, developmental, skeletal, QOL) in the mucopolysaccharidoses, and (d) MRI and biomarker development as outcome measures for the gangliosidoses. The fifth project is a survey study designed to catalog both the odyssey individuals go through before reaching a proper diagnosis and the effectiveness of therapeutics at allowing individuals with lysosomal disease (specifically treated MPS) to live an independent life. Every participant who enrolls in an LDN project is expected to complete the survey studies. Biostatistical analysis assures relevant statistical models for each project.