Children's Hospital Boston George O'Brien Urology Research Center

描述(由申请人提供)： 膀胱过度活动(OAB)，也被称为逼尿肌过度活动(一个膀胱测量学术语)，冲动综合征，或过度活跃的膀胱综合征，是儿童最常见的排尿功能障碍。虽然其病因和潜在的病理生理学仍不清楚，但其临床表现涉及多个方面：从缓慢而隐蔽的发作并逐渐增强的冲动，到可能在很长一段时间内发生的排尿，再到儿童通常在短时间内干燥的突发性、戏剧性的尿失禁发作。根据美国泌尿外科疾病对办公室医生的分析，1992-2000年间，有1,781,506人次去看儿科医生和家庭医生，其尿失禁被编码为任何诊断，每10万名儿童中有2,548人。初步诊断为大小便失禁的儿童共就诊1,126,911次，比率为每100,000名儿童中有1,612名。最近的两项研究强调了认识和治疗儿童OAB的重要性，将其作为成人OAB和痛性膀胱综合征/间质性膀胱炎(PBS/IC)的先兆。一份报告称，儿童良性日间频率综合征和夜间遗尿与成人急迫性尿失禁增加两倍以上有关。同样，第二项研究发现，170名患有尿频、尿急、压力性尿失禁和急迫性尿失禁的女性儿童排尿功能障碍的患病率更高。 项目1的总体目标是：1)使用新的方法来了解儿童OAB的遗传基础，2)在有多个受影响成员的家庭中识别并进行连锁分析，以及3)识别包含导致OAB的突变的候选基因。 我们计划通过以下具体目标来实现我们的目标：目标1.招募患有OAB儿童的多个受影响成员的大家庭。目的2.通过以下方法定位OAB基因的位置：a)对我们先前在成人人群中发现的具有紧迫性和频率的候选基因进行定向突变分析，作为我们的儿科人群的候选OAB基因；b)在OAB分离的家系中进行连锁分析。目的3.在基因组的连锁区域内确定哪些基因含有导致OAB的突变，并将突变类型与临床症状相关联。总体目标将是确定OAB的遗传风险因素，并利用这些信息改进诊断和可能的治疗干预。

DESCRIPTION (provided by applicant): Overactive bladder (OAB), also known as detrusor overactivity (a cystometric term), urge syndrome, or overactive bladder syndrome, is the most common voiding dysfunction in children. While its etiology and underlying pathophysiology remains elusive, the clinical presentation runs across a spectrum: from slow and insidious onset with a gradual increase in the strength of the urge, to voiding that can occur during a long period of time, to sudden, dramatic episodes of incontinence in children who were normally dry over a brief period of time. Based on the Urologic Diseases in America analysis of physicians in office-based settings there were 1,781,506 visits to pediatricians and family practitioners for which urinary incontinence was coded as any diagnosis for 1992-2000, a rate of 2,548 per 100,000 children. A total of 1,126,911 office visits were made by children with a primary diagnosis of incontinence, a rate of 1,612 per 100,000 children. Two recent studies highlight the importance of recognizing and treating pediatric OAB as a precursor to adult OAB and painful bladder syndrome/interstitial cystitis (PBS/IC). One reports that pediatric benign daytime frequency syndrome and nocturnal enuresis were associated with a more than a two-fold increase in adult urge incontinence. Similarly, a second study found a higher prevalence of childhood voiding dysfunction in 170 women with urinary frequency, urgency, stress incontinence and urge incontinence. The overall goals of Project 1 are: 1) To use novel approaches to understand the genetic basis of pediatric OAB, 2) To identify and perform linkage analysis in families with multiple affected members, and 3) To identify candidate genes containing mutations that result in OAB. We plan to attain our goals via the following specific aims: Aim 1. Recruit extended families with multiple affected members of children diagnosed with OAB. Aim 2. Map the locations of OAB genes by: a) performing targeted mutation analysis of candidate genes we have previously identified in the adult population with urgency and frequency as candidate OAB genes in our pediatric population and b) by linkage analysis in families in which OAB is segregating. Aim 3. Identify within linked regions of the genome those genes which harbor mutations that cause OAB and correlate the types of mutations with clinical symptoms. The overall goal will be to identify genetic risk factors for OAB and use this information for improved diagnosis and possible therapeutic intervention.