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1/70. Clinical utility of direct mutation testing for congenital nephrogenic diabetes insipidus in families.

    OBJECTIVE: To ascertain the clinical scenarios in which genetic testing for congenital nephrogenic diabetes insipidus (NDI) by direct detection of mutations might prove valuable, and to assess the use of automated sequencing for testing. methods: We reviewed NDI cases referred to our research laboratory for enrollment in our study of mutations in the AVPR2 gene that is disrupted in the X-linked form of the disease. We selected 5 cases that illustrate the value of genetic testing in different clinical situations. Clinical information was obtained from the patient's personal physicians and the patients' families. Direct automated fluorescent dna sequencing of AVPR2 gene amplification product was used to identify disease-associated mutations in patients. The presence or absence of mutations in family members was then established by using automated sequencing, restriction enzyme analysis, or both. RESULTS: In 2 of the 5 selected cases, the diagnosis of a genetic form of NDI was confirmed by mutation analysis in a sporadic case of an affected boy. In 2 cases, a suspected diagnosis of X-linked NDI was confirmed in an affected girl. In 4 of the cases, 1 or more unaffected female relatives were determined to carry or not to carry the disease-associated gene. In 2 cases, testing of the newborn child of a known or suspected carrier confirmed the clinical suspicion of affected status and justified proactive therapy. In 4 of the 5 cases, the mode of inheritance was not clear from the family history and was established as X-linked by the testing. Assay for restriction sites changed by disease-associated mutations agreed with the automated sequencing results. CONCLUSIONS: We conclude that direct mutation analysis in patients suspected of NDI and in selected family members is indicated. The results of testing can confirm a clinical diagnosis of disease, which may otherwise be difficult to make in girls. It can further establish the mode of inheritance, unambiguously distinguish carriers from noncarriers, and justify special observation or treatment of newborns at risk, thereby averting dehydration and the attendant complications. We also conclude that, with proper controls, automated sequencing is the preferred method of testing, because it is sufficiently robust, sensitive, and adaptable for this short gene with a large variety of causative mutations. ( info)

2/70. Lithium-induced nephrogenic diabetes insipidus.

    BACKGROUND: Lithium can cause nephrogenic diabetes insipidus in up to 20 to 40 percent of patients currently taking the medication, and a subset of these patients will have a persistent concentrating defect long after lithium is discontinued. They are at risk for serious hypernatremia when fluid intake is restricted for any reason. methods: medline as used to search the key words "nephrogenic diabetes insipidus" and "lithium" from 1990 to the present. A case report describes a patient who had been off lithium for 8 years and who developed hypernatremia after she was transferred to a new long-term facility and the staff attempted to control the patient's polydipsia. The diagnosis and treatment of nephrogenic diabetes insipidus are also discussed. RESULTS: This case of persistent nephrogenic diabetes insipidus 8 years after discontinuing lithium is the longest ever reported. Certainly, a number of patients have varying degrees of persistent lithium-related nephrogenic diabetes insipidus. Although pathologic changes are associated with persistent nephrogenic diabetes insipidus, the exact mechanism of the persistent defect is unknown. The mechanism of acute lithium-induced nephrogenic diabetes insipidus while the patient is on lithium is related to changes in intracellular cyclic adenosine monophosphate. CONCLUSIONS: patients currently taking lithium and patients with a remote history of lithium treatment need to be monitored for signs and symptoms of nephrogenic diabetes insipidus. physicians need to be aware of the potential for nephrogenic diabetes insipidus in these patients and care for them appropriately. ( info)

3/70. Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride.

    Nephrogenic diabetes insipidus (NDI) is characterised by the inability of the kidney to concentrate urine in response to arginine vasopressin. The consequences are severe polyuria and polydipsia, often associated with hypertonic dehydration. Intracerebral calcification, seizures, psychosomatic retardation, hydronephrosis, and hydroureters are its sequelae. In this study, four children with NDI were treated with 3 mg/kg/day hydrochlorothiazide and 0.3 mg/kg/day amiloride orally three times a day for up to five years. While undergoing treatment, none of the patients had signs of dehydration or electrolyte imbalance, all showed normal body growth, and there was no evidence of cerebral calcification or seizures. All but one had normal psychomotor development and normal sonography of the urinary tract. However, normal fluid balance was not attainable (fluid intake, 3.8-7.7 l/m2/day; urine output, 2.2-7.4 l/m2/day). The treatment was well tolerated and no side effects could be detected. Prolonged treatment with hydrochlorothiazide/amiloride appears to be more effective and better tolerated than just hydrochlorothiazide. Its efficacy appears to be similar to that of hydrochlorothiazide/indomethacin but without their severe side effects. ( info)

4/70. Effect of DDAVP on nocturnal enuresis in a patient with nephrogenic diabetes insipidus.

    The case of an 8 year old boy with both nocturnal enuresis and nephrogenic diabetes insipidus is presented. diagnosis of nephrogenic diabetes insipidus was based on a typical medical history, the characteristic result of a fluid restriction test, the lack of an effect of 1-desamino-8-D-arginine (DDAVP) on both urine osmolality and plasma coagulation factors and, finally, the detection of a hemizygous missense mutation within the arginine vasopressin (AVP) receptor gene. hydrochlorothiazide treatment and dietary measures reduced the patient's urine volume to one third of its original volume. However, this had no effect on enuresis. The daily intranasal application of DDAVP did not further reduce urine output but dramatically decreased the frequency of bed wetting. This observation contradicts the common notion that the therapeutic effect of DDAVP in nocturnal enuresis is the result of compensation for a nocturnal AVP deficit. Rather, it points to a different mode of action of DDAVP in patients with enuresis. It is hypothesised that central AVP receptors are a target of DDAVP and that they might play an important role in the pathogenesis of nocturnal enuresis. ( info)

5/70. Compound deletion of the rhoGAP C1 and V2 vasopressin receptor genes in a patient with nephrogenic diabetes insipidus.

    The function of small GTPases is fine-tuned by a complex network of regulatory proteins such as gtpase-activating proteins. The C1 gene at Xq28 encodes a protein assumed to function as a Rho GTPase-activating protein (rhoGAP). Characterization of the molecular defect causing X-linked nephrogenic diabetes insipidus (NDI) in a patient revealed a submicroscopic deletion of a 21.5-kb genomic fragment encompassing the entire arginine-vasopressin V2 receptor gene (AVPR2) and most of the C1 gene locus. In the absence of detailed information about the physiological relevance and specific functions of rhoGAP C1, a thorough clinical and laboratory investigation of the patient was performed. Besides clearly defined NDI symptoms caused by deletion of the AVPR2 gene, no major morphological abnormalities as determined by physical examination, radiography, ultrasound, and computed tomographic scan were detected. Extensive analysis of blood chemical, enzyme, and hormone values over a period of 16 years showed no deviations from normal ranges. On the basis of our observations, the rhoGAP C1 protein is not essential for normal development in the human. Because of a predominant expression pattern of the C1 gene in hematopoietic cells, we focused on immunologic and hematologic laboratory parameters of the affected boy and the mother who was found to be heterozygous. Differential white cell counts, including lymphocyte typing, determination of lymphokines, cytokines, and immunoglobulins, as well as numerous leukocyte function tests, showed no pathological findings. Therefore, we postulate that the loss of rhoGAP C1 function is most likely compensated by other members of the GAP family. ( info)

6/70. A novel mutation in the vasopressin V2 receptor gene in a woman with congenital nephrogenic diabetes insipidus.

    A 56-year-old Japanese woman with congenital nephrogenic diabetes insipidus (CNDI) is reported. She was diagnosed with CNDI accompanied by advanced gastric cancer. After total gastrectomy, approximately 500 ml fluid per hour was necessary to prevent dehydration. Urinary volume was decreased by administration of hydrochlorothiazide. We detected a novel mutation in the vasopressin V2 receptor gene of her chromosomal dna. A substitution from G to A was found at the 631 nucleotide position, altering codon 12 from glycine (GGG) to glutamic acid (GAG) in the first extracellular domain. This missense mutation appeared to be the cause of her resistance to arginine vasopressin. ( info)

7/70. A case of nephrogenic diabetes insipidus caused by obstructive uropathy due to prostate cancer.

    Nephrogenic diabetes insipidus (DI) secondary to chronic urinary tract obstruction is a rare disease. The exact cause is unknown but it is likely that increased collecting duct pressures cause damage to the tubular epithelium, resulting in insensitivity to the action of arginine-vasopressin (AVP). A 77-year-old man complaining of polyuria and polydipsia was treated with alpha glucosidase inhibitor under the impression of polyuria due to diabetes mellitus. But his symptoms did not improve. water deprivation and AVP administration study revealed that the patient had nephrogenic DI. urinary tract obstruction due to an enlarged prostate was suggested as a principal cause of nephrogenic DI. The patient underwent transurethral resection of the prostate and bilateral subcapsular orchiectomy. After surgery, the urine osmolarity was normalized and the patient became symptom-free. We report a case of nephrogenic DI due to obstructive uropathy which was cured by surgery eliminating obstruction. ( info)

8/70. A novel splicing mutation in the V2 vasopressin receptor.

    In order to elucidate the molecular basis and the clinical characteristics of X-linked recessive nephrogenic diabetes insipidus (CNDI) in a kindred of Danish descent, we performed direct sequencing of the arginine vasopressin receptor 2 (AVPR2) gene in five members of the family, as well as clinical investigations comprising a fluid deprivation test and a 1-deamino-8-D-arginine-vasopressin (dDAVP) infusion test in the study subject and his mother. We found a highly unusual, novel, de novo 1447A-->C point mutation (gDNA), involving the invariable splice acceptor of the second intron of the gene in both the affected male (hemizygous) and his mother (heterozygous). This mutation is likely to cause aberrant splicing of the terminal intron of the gene, leading to a non-functional AVP receptor. The clinical studies were consistent with such a hypothesis, as the affected subject had a severe insensitivity to both the antidiuretic and the coagulation factors stimulatory actions of AVP and its analogue dDAVP. Direct sequencing of the AVPR2 is an accurate and rapid diagnostic tool for CNDI and early referral of patients for AVPR2 sequencing is therefore strongly suggested. ( info)

9/70. The property of a novel v2 receptor mutant in a patient with nephrogenic diabetes insipidus.

    Nephrogenic diabetes insipidus (NDI) is characterized by resistance of the kidneys to the action of arginine vasopressin (AVP); X-linked recessive NDI is caused by an inactivating mutation of the vasopressin type-2 (V2) receptor. Several missense mutations in the first or second extracellular loop of the V2 receptor have been reported, and some of these mutant receptors were confirmed to have reduced affinities for ligand binding. We detected a novel V2 receptor gene mutation, a substitution of cysteine for arginine-104 (R104C) located in the first extracellular loop of the V2 receptor, in a patient with congenital NDI. Functional analysis by transient expression studies with COS-7 cells showed binding capacity of R104C mutant diminished as 10% of wild type, but binding affinity was strong rather than wild type. In the result of AVP stimulation studies, maximum cAMP accumulation of R104C decreased as 50% of wild type. On the other hand, a designed mutant receptor, substituted serine for arginine-104 as a model of modified R104C mutant receptor removed the influence of the sulfhydryl group in cysteine-104, recovered binding capacity up to 50% of wild type and maximum cAMP accumulation as 82% of wild type. Our study demonstrated that the R104C mutation of the V2 receptor was a cause of NDI. The mechanism of renal resistance to AVP was the reduction of ligand binding, and adenylyl cyclase activation depended on the V2 receptor. In addition, we confirmed that the sulfhydryl group of the cysteine-104 caused most part of R104C mutant receptor dysfunction. ( info)

10/70. Nephrogenic diabetes insipidus persisting 57 months after cessation of lithium carbonate therapy: report of a case and review of the literature.

    OBJECTIVE: To illuminate the natural history of prolonged nephrogenic diabetes insipidus after discontinuation of lithium carbonate treatment and to assess the response to therapy with desmopressin acetate and triamterene-hydrochlorothiazide. methods: We analyzed sequential determinations of serum and urine osmolality, plasma arginine vasopressin, serum sodium, blood urea nitrogen, calcium, ionized calcium, parathyroid hormone, and 24-hour urine volume during a period of 57 months in a 67-year-old woman. RESULTS: Our patient experienced persistent polyuria in conjunction with having repeated serum osmolalities between 300 and 323 mOsm/kg and urine osmolalities between 130 and 208 mOsm/kg. Concomitant plasma arginine vasopressin levels were as high as 12.0 pg/mL, consistent with the diagnosis of nephrogenic diabetes insipidus. Administration of triamterene-hydrochlorothiazide reduced 24-hour urine volume and serum osmolality while increasing urine osmolality. Desmopressin acetate exhibited no effect. CONCLUSION: In this report, we describe the eighth documented case of persistent nephrogenic diabetes insipidus, lasting 57 months after cessation of lithium therapy, and demonstrate a palliative effect of triamterene-hydrochlorothiazide. ( info)
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