PATHOGENESIS AND PATHOPHYSIOLOGY OF FAMILIAL NEUROHYPOPHYSEAL DIABETES

本研究的目的是获得额外的临床和分子遗传学数据，以测试的假设，即家族性神经垂体尿崩症（FNDI）是由于在编码区的加压素-neurophysin II基因的突变，指导生产的突变前激素，积累和破坏大细胞神经元，因为它不能被折叠和有效地处理。 这些研究将在至少14个已知或假定FNDI分离的美国亲属中的所有同意的受影响和未受影响的成员中进行。 受试者将每隔1 - 5年入住临床研究中心，在基础条件下和液体剥夺/高渗盐水输注或水负荷/高渗盐水输注试验期间测量液体摄入量和尿排出量、血浆电解质、血浆和尿加压素、尿水通道蛋白II和异常形式的“大加压素”。 受试者还将接受垂体-下丘脑区域的MRI，并采集血液用于加压素-神经垂体后叶素基因测序。 受影响的受试者将接受去氨加压素（DDAVP）的治疗试验。 少数自发缓解尿崩症的受试者也可能接受催产素或加压素拮抗剂的短期输注，以确定是否发生尿稀释。

The objective of this study is to obtain additional clinical and molecular genetic data to test the hypothesis that familial neurohypophyseal diabetes insipidus (FNDI) is due to mutations in the coding region of the vasopressin-neurophysin II gene that directs the production of a mutant preprohormone that accumulates in and destroys magnocellular neurons because it can not be folded and processed efficiently. The studies will be performed in all consenting affected and unaffected members of at least 14 American kindreds in which FNDI is known or presumed to be segregating. The subjects will be admitted to the Clinical Research Center at 1 to 5 year intervals for measurements of fluid intake and urine output, plasma electrolytes, plasma and urinary vasopressin, urine aquaporin II and abnormal forms of "big vasopressin" under basal conditions and during a fluid deprivation/hypertonic saline infusion or water load/hypertonic saline infusion test. Subjects will also undergo MRI of the pituitary-hypothalamic area and have blood collected for sequencing of the vasopressin-neurophysin gene. Affected subjects will undergo a therapeutic trial of desmopressin (DDAVP). A few subjects who undergo spontaneous remissions of their diabetes insipidus may also receive short infusions of oxytocin or vasopressin antagonists to determine if urinary dilution occurs.