PATHOGENESIS AND PATHOPHYSIOLOGY OF FAMILIAL NEUROHYPOPHYSEAL DIABETES

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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 direct 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.