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1.
Pediatrics ; 108(1): E5, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11433084

ABSTRACT

OBJECTIVE: To characterize a rare inherited hypokalemic salt-losing tubulopathy with linkage to chromosome 1p31. METHODS: We conducted a retrospective analysis of the clinical data for 7 patients in whom cosegregation of the disease with chromosome 1p31 had been demonstrated. In addition, in 1 kindred, prenatal diagnosis in the second child was established, allowing a prospective clinical evaluation. RESULTS: Clinical presentation of the patients was homogeneous and included premature birth attributable to polyhydramnios, severe renal salt loss, normotensive hyperreninemia, hypokalemic alkalosis, and excessive hyperprostaglandin E-uria, which suggested the diagnosis of hyperprostaglandin E syndrome/antenatal Bartter syndrome. However, the response to indomethacin was only poor, accounting for a more severe variant of the disease. The patients invariably developed chronic renal failure. The majority had extreme growth retardation, and motor development was markedly delayed. In addition, all patients turned out to be deaf. CONCLUSION: The hypokalemic salt-losing tubulopathy with chronic renal failure and sensorineural deafness represents not only genetically but also clinically a disease entity distinct from hyperprostaglandin E syndrome/antenatal Bartter syndrome. A pleiotropic effect of a single gene defect is most likely causative for syndromic hearing loss.


Subject(s)
Chromosomes, Human, Pair 1/genetics , Deafness/genetics , Dinoprostone/metabolism , Growth Disorders/genetics , Hypokalemia/genetics , Kidney Failure, Chronic/genetics , Renal Tubular Transport, Inborn Errors/diagnosis , Renal Tubular Transport, Inborn Errors/genetics , Adolescent , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Bartter Syndrome/genetics , Child , Child, Preschool , Consanguinity , Creatinine/blood , Cyclooxygenase Inhibitors/therapeutic use , Dinoprostone/urine , Diuresis , Female , Genetic Linkage , Haplotypes , Humans , Hypokalemia/drug therapy , Indomethacin/therapeutic use , Infant , Kidney/diagnostic imaging , Kidney/pathology , Kidney/ultrastructure , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/drug therapy , Lebanon , Male , Pedigree , Phenotype , Renal Tubular Transport, Inborn Errors/diagnostic imaging , Renal Tubular Transport, Inborn Errors/drug therapy , Renal Tubular Transport, Inborn Errors/pathology , Retrospective Studies , Syndrome , Treatment Outcome , Turkey , Ultrasonography
2.
J Clin Endocrinol Metab ; 85(4): 1703-10, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10770218

ABSTRACT

X-Linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by the excretion of abnormal large volumes of diluted urine mainly caused by mutations in the V2 vasopressin receptor (AVPR2) gene. By screening NDI patients for mutations within the AVPR2 gene we have identified three novel (I46K, F105V, I130F) and four recurrent (D85N, R106C, R113W, Q225X) mutations. In addition, a recurrent missense mutation (A147T) within the aquaporin-2 gene was identified in a female patient with autosomal recessive NDI associated with sensorineural deafness. Selected clinical data of the NDI patients were compared with the results from the in vitro studies. Functional analysis of I46K and I130F revealed reduced maximum agonist-induced cAMP responses as a result of an improper cell surface targeting. In contrast, the F105V mutation is delivered to the cell surface and displayed an unchanged maximum cAMP response, but impaired ligand binding abilities of F105V were reflected in a shifted concentration-response curve toward higher vasopressin concentrations. As the extracellularly located F105 is highly conserved among the vasopressin/oxytocin receptor family, functional analysis of this residue implicates an important role in high affinity agonist binding.


Subject(s)
Aquaporins/genetics , Diabetes Insipidus, Nephrogenic/genetics , Mutation , Receptors, Vasopressin/genetics , X Chromosome , Amino Acid Sequence , Animals , Aquaporin 2 , Aquaporin 6 , Arginine Vasopressin/metabolism , COS Cells , Child , Child, Preschool , DNA Mutational Analysis , Deoxyribonucleases, Type II Site-Specific/metabolism , Female , Genetic Linkage , Humans , Infant , Male , Molecular Sequence Data , Mutagenesis, Site-Directed , Mutation, Missense , Pedigree , Polymerase Chain Reaction , Receptors, Vasopressin/chemistry , Sequence Alignment , Transfection
3.
Hum Mutat ; 14(2): 163-74, 1999.
Article in English | MEDLINE | ID: mdl-10425039

ABSTRACT

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.


Subject(s)
Diabetes Insipidus, Nephrogenic/genetics , GTP-Binding Proteins/genetics , GTPase-Activating Proteins , Gene Deletion , Receptors, Vasopressin/genetics , Adolescent , Aging/blood , Blood Cell Count , DNA Mutational Analysis , Diabetes Insipidus, Nephrogenic/blood , Hematopoietic System/metabolism , Humans , Immunophenotyping , Leukocytes/immunology , Leukocytes/metabolism , Male , Phenotype , Polymerase Chain Reaction , Sequence Deletion , X Chromosome/genetics
4.
J Pediatr ; 130(2): 240-4, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9042126

ABSTRACT

BACKGROUND: More and progressively smaller preterm infants are taken out of the incubator and placed skin to skin on their mother's chest to promote bonding, despite concerns that the infants are exposed to cold during this intervention. OBJECTIVE: To test the hypothesis that skin-to-skin care is a cold stress for preterm infants weighing less than 1500 gm, with a decrease in rectal temperature, a decrease in peripheral skin temperature, or an increase in oxygen consumption compared with conditions monitored during incubator care. STUDY DESIGN: We studied 22 stable, spontaneously breathing preterm infants weighing less than 1500 gm (appropriate in size for gestational age), who had their first skin-to-skin care in the first week of life. We continuously measured rectal temperature, peripheral skin temperature (foot), and oxygen consumption (indirect calorimetry) for 1 hour in a thermoneutral incubator, during 1 hour of skin-to-skin care, and for another hour in the incubator. Mean values for the three periods were compared by analysis of variance. RESULTS: During skin-to-skin care the mean rectal temperature was 0.2 degree C (p < 0.01) and the peripheral skin temperature was 0.6 degree C (p < 0.01) higher than during the preceding hour in the incubator. Back in the incubator, body temperatures returned to values recorded before skin-to-skin care. Oxygen consumption during skin-to-skin care (6.1 +/- 0.9 ml/kg per minute) was not significantly higher than in the incubator (5.8 +/- 0.8 ml/kg per minute). CONCLUSION: For stable preterm infants weighing less than 1500 gm and less than 1 week of age, 1 hour of skin-to-skin care is not a cold stress compared with care in a thermoneutral incubator.


Subject(s)
Body Temperature , Infant Care/methods , Infant, Premature/physiology , Infant, Very Low Birth Weight/physiology , Oxygen Consumption , Breath Tests , Calorimetry, Indirect , Cold Temperature/adverse effects , Evaluation Studies as Topic , Humans , Incubators, Infant , Infant, Newborn , Rectum , Stress, Physiological/physiopathology , Time Factors
5.
Pediatr Res ; 41(1): 139-44, 1997 Jan.
Article in English | MEDLINE | ID: mdl-8979303

ABSTRACT

Complete sampling of expired air is essential for accurate O2 consumption(CO2 production) [VO2(VCO2)] measurements with flow-through indirect calorimetry. In preterm infants complete sampling is critical, because only low sampling flows can be used. The accuracy of the various breath sampling systems at low flows and their patient compatibility is untested. We therefore measured 1) the accuracy of VO2(VCO2) measurements with a face mask, a head hood, and a canopy in vitro at low sampling flows; 2) the effect of breathing on measurements with the face mask; and 3) the effect of breath sampling systems on activity and body temperature of preterm infants. VO2(VCO2) were measured with a Deltatrac II. In vitro we used a methanol miniburner incorporated into a doll, which could simulate low VO2(VCO2) and tidal breathing. In vivo we studied seven preterm infants < 1500 g. With the face mask VO2(VCO2) measurements were accurate at a flow of 3 L/min (error -1 +/- 0.8%), when tidal volume was < 15 mL/breath and the distance between mask and manikin < 1 cm. With hood and canopy VO2(VCO2) were underestimated at a flow of 3 L/min (error -13 +/- 1% and -14 +/- 5%), and results were markedly influenced by body position. For accurate measurements, the hood needed a flow of 4.5 L/min, the canopy 8.3 L/min. In vivo the face mask did not increase heart rate, respiration, activity, or rectal temperature, but hood and canopy increased rectal temperature by 0.3-0.4 degree C. For VO2(VCO2) measurements in infants < 1500 g, a face mask should be used, which is accurate at low flows and does not change body temperature. Accuracy at low flows and patient compatibility of breath sampling systems should be evaluated and reported for VO2(VCO2) measurements in preterm infants.


Subject(s)
Breath Tests/instrumentation , Calorimetry, Indirect/instrumentation , Carbon Dioxide/metabolism , Infant, Very Low Birth Weight/physiology , Oxygen Consumption , Respiration, Artificial/instrumentation , Body Temperature , Humans , Infant, Newborn , Manikins , Reproducibility of Results
6.
Quintessence Int (Berl) ; 3(4): 61-8, 1972 Apr.
Article in English | MEDLINE | ID: mdl-4502955
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