Rare early onset lower urinary tract disorders

问题：英国许多儿童患有严重的膀胱问题，导致尿床、大小便失禁、尿液感染，甚至严重的肾脏损伤。事实上，罕见的膀胱疾病是导致儿童肾衰竭的最常见原因，这些儿童只能通过透析和移植来维持生命。多达三分之一患有严重膀胱排空问题的儿童也有便秘。肠道和膀胱问题对孩子的自尊、教育和社会关系的影响比几乎任何其他医学疾病都要大。我们解决这个问题的方法。基因是我们细胞中的遗传指令，为我们的身体发育提供信息。我们知道许多基因在膀胱和输尿管(连接肾脏的管子)的发育和工作中起着重要作用。我们发现，在患有罕见的严重膀胱问题的儿童中，这些基因中的一些发生了变化。然而，我们已经从许多我们仍然没有遗传答案的儿童那里收集了样本和临床信息。这代表着一个重大的未得到满足的需求。通过这个罕见的疾病节点，我们将在英国各地创建一个临床医生和研究人员网络，从受这些疾病影响的儿童那里收集样本和信息，创建一个受影响个人和基因样本的登记，以供进一步研究。我们将作为一个协作团队来解决这些具有挑战性的问题，并培训和支持下一代研究人员和临床医生来照顾受影响的家庭。我们提出了三个答案：1.使用新型的基因分析，其中我们可以研究细胞中遗传物质的结构变化，以找到严重遗传性膀胱问题的原因；2.从手术中采集的样本中，观察患有严重膀胱外翻的儿童的膀胱和输尿管中基因是如何打开和关闭的，并将这些模式与健康儿童进行比较。这将让我们深入了解器官是如何发育的，如何以及为什么会出错；以及3.我们将寻找新的令人兴奋的方法将基因输送到身体，以便他们可以使用一种称为基因疗法的方法来纠正这些疾病。找到负责的基因将使我们能够：1.给家庭提供他们孩子问题的原因；2.对其他家庭成员进行简单的基因测试，看看他们是否需要体检，以检测并防止病情发展为严重的膀胱和肾脏疾病；以及3.开始了解儿童受到这些问题影响的原因，这将有助于开发新的治疗方法。此外，了解罕见的遗传性膀胱问题可以解释为什么儿童更常见的问题，如尿床和尿液感染，这些问题影响了近100万英国儿童。我们将与受影响的家庭组织会议，讨论我们的工作，并征求意见，以指导我们处理这些研究的方式，并通过Eric、儿童肠道和膀胱慈善等慈善机构分享有关他们的信息。2018年NHS英格兰大陆护理卓越指南强调了尿失禁患者临床护理的不平等和改善的必要性。由于严重的遗传性膀胱疾病可能会影响多个家庭成员，其影响更大。由于大多数是以常染色体隐性遗传(从每个未受影响的父母那里继承的一种基因变化)模式遗传的，这些疾病在家庭婚姻发生的社区更常见。在英国，巴基斯坦裔家庭承受着沉重的负担。在2017年英国健康概况报告中，英属巴基斯坦人的婴儿死亡率增加了三倍，该社区健康状况较差的其他指标也增加了三倍。因此，支持对这些疾病的研究将对弱势群体的健康产生重大影响。

The problem.Many children in the UK suffer with significant bladder problems that result in bed-wetting, incontinence, urine infections and even severe kidney damage. In fact, rare bladder conditions are the commonest cause of kidney failure in children who can only be kept alive by dialysis and transplantation. Up to one in three children with severe bladder emptying problems also have constipation. Bowel and bladder problems have more impact than almost any other medical condition on children's self-esteem, education and social relationships.Our approach to the problem.Genes are the inherited instructions in our cells providing the information for how our bodies develop. We know that many genes are important in how the bladder and ureters (tubes connected to the kidneys) develop and work. We have discovered changes in a number of these genes in children with rare severe bladder problems. However, we have collected samples and clinical information from many children where we still do not have a genetic answer. This represents a significant unmet need. Through this rare disease node we will create a network of clinicians and researchers across the UK to collect samples and information from children affected by these conditions creating a registry of affected individuals and genetic samples for further study. We will work as a collaborative team to address these challenging problems and train and support the next generation of researchers and clinicians to care for affected families.We propose three answers: 1. to use new types of genetic analysis, where we can study structural changes in the genetic material in a cell, to find the causes of severe inherited bladder problems; 2. to look at how genes are switched on and off in the bladder and ureters in children with a severe condition called bladder exstrophy from samples taken at surgery and compare these patterns to healthy children. This will give us an insight into how the organs develop and how and why this may go wrong; and 3. we will look at new exciting ways to deliver genes to the body so that they may correct these conditions using an approach called gene therapy.Finding the responsible genes will allow us to: 1. give families the reason for their children's problems; 2. do simple genetic tests on other family members to see if they may require check-ups to detect and prevent the progression to severe bladder and kidney disease; and 3. start to understand the reasons that children are affected by these problems which will help to develop novel treatments. Furthermore, understanding rare inherited types of bladder problems can provide reasons as to why children have more common problems like bed-wetting and urine infections, which affect nearly one million UK children.We will organise meetings with affected families to discuss our work and seek input to guide the way that we approach these studies and share information about them through charities like ERIC, the Children's Bowel and Bladder Charity. The 2018 NHS England guidance on Excellence in Continence Care highlights the inequalities and need for improvements in clinical care for individuals with urinary and bowel incontinence.Because severe inherited bladder disorders can affect multiple family members their impact is greater. As most are inherited in an 'autosomal recessive' pattern (a genetic change inherited from each unaffected parent), these conditions are more common in communities where marriage within families occurs. In the UK there is a significant burden in families of Pakistani origin. In the Health Profile for England Report 2017, there was a threefold increased infant mortality in British Pakistanis and other measures of poorer health in this community. Therefore, supporting research in these disorders will have a major health benefit in a disadvantaged community.