Study of the Pathogenesis and Pathophysiology of Familial Neurohypophyseal Diabetes Insipidus

Diabetes Insipidus, Diabetes Insipidus, Neurohypophyseal

diabetes insipidus, endocrine disorders, rare disease

OBJECTIVES: I. Determine whether diverse mutations of the vasopressin-neurophysin II (AVP-NPII) gene cause autosomal dominant familial neurohypophyseal diabetes insipidus by directing the production of an abnormal preprohormone. II. Determine whether the AVP-NPII gene-directed preprohormone accumulates and destroys magnocellular neurons because it cannot be folded and processed efficiently.

PROTOCOL OUTLINE: This project involves 2 clinical studies. Members of known kindreds participate in Study I; members of kindreds who have not been surveyed, genotyped, or phenotyped participate in Study II. In Study I, participants undergo clinical, hormonal, radiologic, and biochemical studies. Assessment on unrestricted fluid intake includes body weight, urine volume, osmolality, creatinine, sodium, potassium, urea, glucose, arginine-vasopressin (AVP), oxytocin, and aquaporin-II. Participants with diabetes insipidus (DI) undergo a standard fluid deprivation test; those without DI undergo standard water load and hypertonic saline testing. Previously untreated DI patients may be given intranasal or subcutaneous desmopressin or oral chlorpropamide (adults only) for 2 or 3 days. Magnetic resonance imaging of the pituitary-hypothalamic area is performed on all patients with and without gadolinium. Infants and children are studied annually for the first 5 years or until they develop DI. Affected adults are studied every 2-5 years. Unaffected adults are re-tested only if they subsequently report de novo symptoms suggestive of DI. In Study II, participants undergo similar genotype and phenotype testing. Kindreds demonstrating the familial neurohypophyseal diabetes insipidus phenotype and genotype are added to Study I. Kindreds found to have a different type of DI are directed into a companion protocol.

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United States