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Familial neurohypophyseal diabetes insipidus: Relation of phenotype to genotype
$2-B1-1-05
PATHOPHYSIOLOGICAL SIGNIFICANCE OF ANTI-DIURETIC HORMONES AND ITS RELATED SUBSTANCES IN CLINICAL DISORDERS T.Terano, A.Hiral, T.Oeda, M. Nishlmura, A.Seya, Y.Tamura, S.Yoshida Second Department of Internal Medicine, Chiba Univ. School of Medicine, Chiba,Japan (1)Morphological significance of pituitary gland in aged subjects: We have investigated the morphological characteristics of the pituitary glands of 99 aged subjects by magnetic resonance imaging(MRI). In about 30% of aged subjects without any sign or symptoms of diabetes insipidus (DI), posterior bright signal(PBS) in T1 weighted MRI was not detected. Disappearance of PBS is reported to be characteristic for DI. The ability of ADH secretion was preserved in these aged subjects. Therefore we should be careful to evaluate the MRI of pituitary gland in aged subjects, considering the physiological changes observed in the aged subjects. Empty sella was seen in18% of aged subjects. But the basal values of anterior pituitary ,thyroid and adrenocortical hormones were normal. (2)The effect of the administration of specific ADH V1 antagonist on the albuminuria in diabetic patients: We have administered OPC-21268, non-peptide specific ADH V1 antagonist, to 68 diabetic patients with early diabetic nephropathy for 8 weeks. In one group of the patients whose pretreatment urinary albumin secretion was 40-160mg/g.creatinine, OPC-21268 administration significantly reduced the urinary secretion of albumin without altering blood pressure. These data suggests the clinical importance and usefulness of V1 antagonist for the prevention of early diabetic nephropathy. (3)Gene analysis of ADH V2 receptor in the patients of congenital nephrogenic DI: Using genomic DNA of V2 receptor from the patients of 3 families of nephrogenic DI, whole V2 receptor gene was amplified by PCR and sequence was clarified by dideoxy method. In the first family, point mutation was found at nucleotide 694(G to A) and then Trp208 was changed to stop codon and premature termination might be seen at 5th trans membrane domain. In the second family mutation was not found. In the third family, point mutation was found at nucleotide 333(G to A) and then Va188 was changed to Met. In two out of these 3 families, point mutation of V2 receptor were found and these changes might lead the abnormal signal transduction through V2 receptor.
$2-B1-1-06 FAMILIAL NEUROHYPOPHYSEAL DIABETES INSIPIDUS: RELATION OF PHENOTYPE TO GENOTYPE G. L. Robertson', L. Kovacs2, S. Rittig 3, E.B. Pedersen 3 1) Dept. of Medicine and Neurology, Northwestern Univ. Medical School, Chicago, USA 2) Dept. of Pediatrics, Comenius Univ. Bratislava, SL 3) Dept. of Medicine and Nephrology C, Skejby Univ. Hospital in Aarhus, DK Familial neurohypophyseal diabetes insipidus (FNDI) is a disease characterized by polyuria, potydipsia and a deficiency of the antidiuretic hormone, arginine vasopressin (AVP). It is transmitted in an autosomal dominant mode, usually manifests in the first few years of life and, in some kindreds at least, is associated with degeneration of the neurons that make AVP. FNDI has been linked to a variety of mutations in all 3 exons of the gene that codes for the AVP-neurophysin-II-copeptinprecursor (AVP-NPII-CP). However, it is not known if the various abnormalities in AVPNPII-CP structure predicted by these mutations result in appreciably different disease phenotypes. We now report the clinical findings in 52 affected and 65 unaffected members of 4 genetically heterogenous kindreds with FNDI. Two kindreds (Po/Ra) have the same missense mutation at base 279 in exon 1 (G to A, changing ALA to THR in the -1 position of the signal peptide). The other two (Hu/Ha) have missense mutations at base 1859 or 1883 in exon 2 (G to A, changing GLY to ARG at position 57 in NPII; or G to T, changing GLY to CYS at position 65 in NPII). We found that the plasma and/or urinary AVP response to osmotic stimulation was deficient in all of the genetically affected adults tested (23 from Po/Ra, 12 from Ha/Hu) and was normal in all 36 of their unaffected relatives. However, the AVP deficiency was partial in more adults with the mutation in exon 1 (4) than in exon 2 (0) even though the deficiency increased with age in all 4 of the kindred-Po patients that we retested. The age of onset also differed slightly. In kindreds Po/Ra, it ranged from 2.5 to 9 yrs. When tested before the onset of FNDI, two of them secreted normal amounts of intact AVP as well as abnormally large amounts or types of "big" AVP. In kindreds Ha/Hu, the FNDI usually began too early for accurate dating but it was definitely present before 2 years of age in at least 4 (20%) of them. Spontaneous remission of FNDI during middle age was reported by at least one male from all 4 kindreds. The 3 who were tested had a normal 24 hour urine volume and osmolality with impaired urinary dilution despite a severe deficiency of AVP and normal renal and adrenal function. We conclude that all 3 genotypes are fully penetrant and produce similar FNDI phenotypes except for a slightly slower development of the AVP deficiency in patients with the exon 1 mutation. Thus, mutations that alter the signal peptide of the precursor may be slightly less disruptive of cellular processes than those that alter the NP moiety. Spontaneous remissions, however, occur largely if not only in males, are unrelated to genotype and are not due to regeneration of AVP secretory capacity or any recognized cause of AVP independent urinary concentration.
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PATHOPHYSIOLOGICAL SIGNIFICANCE OF ANTI-DIURETIC HORMONES AND ITS RELATED SUBSTANCES IN CLINICAL DISORDERS T.Terano, A.Hiral, T.Oeda, M. Nishlmura, A.Seya, Y.Tamura, S.Yoshida Second Department of Internal Medicine, Chiba Univ. School of Medicine, Chiba,Japan (1)Morphological significance of pituitary gland in aged subjects: We have investigated the morphological characteristics of the pituitary glands of 99 aged subjects by magnetic resonance imaging(MRI). In about 30% of aged subjects without any sign or symptoms of diabetes insipidus (DI), posterior bright signal(PBS) in T1 weighted MRI was not detected. Disappearance of PBS is reported to be characteristic for DI. The ability of ADH secretion was preserved in these aged subjects. Therefore we should be careful to evaluate the MRI of pituitary gland in aged subjects, considering the physiological changes observed in the aged subjects. Empty sella was seen in18% of aged subjects. But the basal values of anterior pituitary ,thyroid and adrenocortical hormones were normal. (2)The effect of the administration of specific ADH V1 antagonist on the albuminuria in diabetic patients: We have administered OPC-21268, non-peptide specific ADH V1 antagonist, to 68 diabetic patients with early diabetic nephropathy for 8 weeks. In one group of the patients whose pretreatment urinary albumin secretion was 40-160mg/g.creatinine, OPC-21268 administration significantly reduced the urinary secretion of albumin without altering blood pressure. These data suggests the clinical importance and usefulness of V1 antagonist for the prevention of early diabetic nephropathy. (3)Gene analysis of ADH V2 receptor in the patients of congenital nephrogenic DI: Using genomic DNA of V2 receptor from the patients of 3 families of nephrogenic DI, whole V2 receptor gene was amplified by PCR and sequence was clarified by dideoxy method. In the first family, point mutation was found at nucleotide 694(G to A) and then Trp208 was changed to stop codon and premature termination might be seen at 5th trans membrane domain. In the second family mutation was not found. In the third family, point mutation was found at nucleotide 333(G to A) and then Va188 was changed to Met. In two out of these 3 families, point mutation of V2 receptor were found and these changes might lead the abnormal signal transduction through V2 receptor.
$2-B1-1-06 FAMILIAL NEUROHYPOPHYSEAL DIABETES INSIPIDUS: RELATION OF PHENOTYPE TO GENOTYPE G. L. Robertson', L. Kovacs2, S. Rittig 3, E.B. Pedersen 3 1) Dept. of Medicine and Neurology, Northwestern Univ. Medical School, Chicago, USA 2) Dept. of Pediatrics, Comenius Univ. Bratislava, SL 3) Dept. of Medicine and Nephrology C, Skejby Univ. Hospital in Aarhus, DK Familial neurohypophyseal diabetes insipidus (FNDI) is a disease characterized by polyuria, potydipsia and a deficiency of the antidiuretic hormone, arginine vasopressin (AVP). It is transmitted in an autosomal dominant mode, usually manifests in the first few years of life and, in some kindreds at least, is associated with degeneration of the neurons that make AVP. FNDI has been linked to a variety of mutations in all 3 exons of the gene that codes for the AVP-neurophysin-II-copeptinprecursor (AVP-NPII-CP). However, it is not known if the various abnormalities in AVPNPII-CP structure predicted by these mutations result in appreciably different disease phenotypes. We now report the clinical findings in 52 affected and 65 unaffected members of 4 genetically heterogenous kindreds with FNDI. Two kindreds (Po/Ra) have the same missense mutation at base 279 in exon 1 (G to A, changing ALA to THR in the -1 position of the signal peptide). The other two (Hu/Ha) have missense mutations at base 1859 or 1883 in exon 2 (G to A, changing GLY to ARG at position 57 in NPII; or G to T, changing GLY to CYS at position 65 in NPII). We found that the plasma and/or urinary AVP response to osmotic stimulation was deficient in all of the genetically affected adults tested (23 from Po/Ra, 12 from Ha/Hu) and was normal in all 36 of their unaffected relatives. However, the AVP deficiency was partial in more adults with the mutation in exon 1 (4) than in exon 2 (0) even though the deficiency increased with age in all 4 of the kindred-Po patients that we retested. The age of onset also differed slightly. In kindreds Po/Ra, it ranged from 2.5 to 9 yrs. When tested before the onset of FNDI, two of them secreted normal amounts of intact AVP as well as abnormally large amounts or types of "big" AVP. In kindreds Ha/Hu, the FNDI usually began too early for accurate dating but it was definitely present before 2 years of age in at least 4 (20%) of them. Spontaneous remission of FNDI during middle age was reported by at least one male from all 4 kindreds. The 3 who were tested had a normal 24 hour urine volume and osmolality with impaired urinary dilution despite a severe deficiency of AVP and normal renal and adrenal function. We conclude that all 3 genotypes are fully penetrant and produce similar FNDI phenotypes except for a slightly slower development of the AVP deficiency in patients with the exon 1 mutation. Thus, mutations that alter the signal peptide of the precursor may be slightly less disruptive of cellular processes than those that alter the NP moiety. Spontaneous remissions, however, occur largely if not only in males, are unrelated to genotype and are not due to regeneration of AVP secretory capacity or any recognized cause of AVP independent urinary concentration.
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