NATURAL HISTORY OF ATAXIA-TELANGIECTASIA

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。共济失调-毛细血管扩张症(A-T)是一种罕见的常染色体隐性遗传病，可导致进行性神经变性、免疫缺陷和恶性倾向。这种疾病的研究因其罕见而受到阻碍，以至于即使是最大的医疗中心也只跟踪了不到12名患者。四年前，我们在约翰霍普金斯大学建立了A-T临床中心，这是儿科临床研究单位和私人基金会A-T儿童项目的合资企业。自那以后，我们已经接诊了来自美国各地以及加拿大、墨西哥、南美和中美洲、欧洲和非洲的250多名患者。我们已经利用这个庞大的患者群来更仔细地定义A-T的表型。我们已经证明，A-T的诊断通常是在共济失调发病数年后做出的，因为大多数临床医生直到毛细血管扩张出现时才怀疑诊断。我们开发了一种用于神经疾病临床评估的评分表。这对识别A-T变异很有用，对监测未来的治疗试验也是不可或缺的。我们发现了极高频率的寡克隆性丙种球蛋白病和高丙种球蛋白血症。这些以前没有被认识到，可能是A-T患者免疫系统过早衰老的前哨特征。正在进行的研究将有助于确定慢性/复发性肺部感染的病因，并确定基因和表型之间的关系。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ataxia-telangiectasia (A-T) is a rare, autosomal recessive disorder that causes progressive neurodegeneration, immunodeficiency, and predisposition to malignancy. Studies of this disease have been hampered by its rarity, so that even the largest medical centers have followed fewer than a dozen patients. Four years ago, we established the A-T Clinical Center at Johns Hopkins as a joint venture between the Pediatric Clinical Research Unit and a private foundation, the A-T Children's Project. We have since seen more than 250 patients from all parts of the United States, as well as Canada, Mexico, South and Central America, Europe and Africa. We have used this large patient base to more carefully define the phenotype of A-T. We have documented that the diagnosis of A-T is usually made years after the onset of ataxia because most clinicians do not suspect the diagnosis until telangiectasia appear. We have developed a scoring scale for the clinical assessment of neurologic disease. This has been useful for recognizing A-T variants, and will be indispensable for monitoring future therapeutic trials. We have identified extraordinarily high frequencies of oligoclonal gammopathy and hypergammaglobulinemia. These were previously unrecognized and may be sentinel features of premature senescence of the immune system in patients with A-T. Studies in progress will help to define the etiology of chronic/recurrent pulmonary infections, and define the relationship between genotype and phenotype.