Two cases of hereditary diabetes insipidus, with an autopsy finding in one

Abstract

Two cases of hereditary diabetes insipidus (DI) are described, with an autopsy finding in one. The patients were brothers and 7 other relatives had symptoms of DI. The transmission of the disease in this family seemed to be an autosomal dominant trait with incomplete penetration. Both patients had the incomplete type of DI, which is diagnosed by the response of plasma AVP and the change in Uosm/Posm to 14 h water deprivation.The post-mortem examination in Case 1 showed that there was no atrophy of the supraoptic nucleus and paraventricular nucleus, but immunohistochemical studies

Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum.

“…Thus, it appears that some children with FNDI are born with normally functioning AVP-producing neurons, but lose this activity over time. Second, in vivo imaging studies (17), and autopsy studies (19)(20)(21) are consistent with selective loss of AVP neurons and their axonal extensions into the neurohypophysis. Third, the A(Ϫ1)T signal peptide mutation resulted in an abnormally processed precursor protein in vitro (10), which was postulated to be accumulated within the ER and cytotoxic.…”

“…Autopsy studies in patients with FNDI have suggested a paucity of AVP-producing neurons in the hypothalamus (19)(20)(21), and this has led to the suggestion that the mutations exert a cytotoxic effect. Consistent with the loss of AVP neurons, some patients with FNDI lack the characteristic bright spot on magnetic resonance imaging of the posterior pituitary (17).…”

A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons

“…Symptoms of diabetes insipidus, such as polyuria, polydipsia, and thirst, usually manifest several months or years after birth. A limited number of autopsy studies have reported a paucity of AVP-producing neurons in the hypothalamus of patients with FNDI (2)(3)(4)(5), leading to the hypothesis that progressive degeneration of AVP-producing cells might be involved in the pathogenesis of the disease.…”

Dominant pro-vasopressin mutants that cause diabetes insipidus form disulfide-linked fibrillar aggregates in the endoplasmic reticulum

“…Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) shows a high penetrance, with symptoms beginning weeks to months after birth. Postmortem histological studies of affected individuals have shown degeneration of the vasopressinergic magnocellular neurons (Bergeron et al, 1991;Braverman et al, 1965;Green et al, 1967;Nagai et al, 1984). A knock-in mouse model expressing the human pathogenic mutant C67X (Cys67 of NPII mutated to a stop codon) confirmed the neurotoxic effect of the mutant protein on vasopressinergic cells (Russell et al, 2003), but the mechanism causing cell death remains unknown.…”