Rare early onset lower urinary tract disorders

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.

In our proposed rare early onset lower urinary tract (REOLUT) node, we propose three initial projects to address key questions underpinning REOLUT disorders. These studies will form the foundation for major research funding applications; make an immediate impact for affected individuals and their families; and form the basis for future related research into the causes and potential treatment of REOLUT disorders. First, we will use a combination of techniques to determine the genes and genetic mechanisms resulting in REOLUT disorders. We will work with RaDaR to create a national registry to ascertain affected individuals, collecting clinical data and samples; we will interrogate whole genome sequence data to identify novel causes of REOLUT disorders; generate methylation profiles of samples taken from patients with bladder exstrophy and study the impact of structural genomic variants on REOLUT disorders. Second, we will use novel techniques to examine the single cell expression patterns from bladder tissues taken at surgery from patients with bladder exstrophy to create an atlas to more fully understand the pathobiology of this devastating disease. Third, we will explore techniques to transfer genes to human cells using urofacial syndrome as an exemplar to correct function and as a precursor to clinical trials of gene therapy in affected children. Each of these projects address the major challenges faced by individuals affected by the REOLUT disorders by aiming to improve diagnosis, understanding the underlying causes, and informing new treatments and they have been supported in discussions with patient advocates and the clinical community. The node will create a vibrant national community for training the next cadre of researchers and clinicians in REOLUT disorders and a forum to drive forward major advances in our understanding and treatment of these under-researched conditions.