Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting.

Familial renal glucosuria (FRG) is an inherited renal tubular disorder characterized by persistent isolated glucosuria in the absence of hyperglycemia. Mutations in the sodium/glucose co-transporter SGLT2 coding gene, SLC5A2, were recently found to be responsible for the disorder. Here, we report the molecular and phenotype study of five unrelated FRG families. Five patients were identified and their family members screened for glucosuria. SLC5A2 coding region of index cases was polymerase chain reaction amplified and sequenced. Five different mutations are reported, including four novel alleles. The IVS12+1G>A and p.A102V alleles were identified in homozygosity in index patients of two unrelated families. A proband from another family was compound heterozygous for the p.R132H and p.A219T mutations, and the heterozygous p.Q167fsX186 frameshift allele was the only mutation detected in the affected individual from an additional pedigree. For the remaining family no mutations were detected. The patient homozygous for the p.A102V mutation had glucosuria of 65.6 g/1.73 m(2)/24 h, evidence of renal sodium wasting, mild volume depletion, and raised basal plasma renin and serum aldosterone levels. Our findings confirm previous observations that in FRG, transmitted as a codominant trait with incomplete penetrance, most mutations are private. In the only patient with massive glucosuria in our cohort there was evidence evocative of renin-angiotensin aldosterone system activation by extracellular volume depletion induced by natriuresis. Definite proof of renin-angiotensin aldosterone system activation in FGR should rely on evaluation of additional patients with massive glucosuria.

Characterization of the NPHP1 locus: mutational mechanism involved in deletions in familial juvenile nephronophthisis.

Familial juvenile nephronophthisis is an autosomal recessive, genetically heterogeneous kidney disorder representing the most frequent inherited cause of chronic renal failure in children. A gene, NPHP1, responsible for approximately 85% of the purely renal form of nephronophthisis, has been mapped to 2q13 and characterized. The major NPHP1 gene defect is a large homozygous deletion found in approximately 80% of the patients. In this study, by large-scale genomic sequencing and pulsed-field gel electrophoresis analysis, we characterized the complex organization of the NPHP1 locus and determined the mutational mechanism that results in the large deletion observed in most patients. We showed that the deletion is 290 kb in size and that NPHP1 is flanked by two large inverted repeats of approximately 330 kb. In addition, a second sequence of 45 kb located adjacent to the proximal 330-kb repeat was shown to be directly repeated 250 kb away within the distal 330-kb repeat deleting the sequence tag site (STS) 804H10R present in the proximal copy. The patients' deletion breakpoints appear to be located within the 45-kb repeat, suggesting an unequal recombination between the two homologous copies of this smaller repeat. Moreover, we demonstrated a nonpathologic rearrangement involving the two 330-kb inverted repeats found in 11 patients and, in the homozygous state, in 2 (1.3%) control individuals. This could be explained by interchromosomal mispairing of the 330-kb inverted repeat, followed by double recombination or by a prior intrachromosomal mispairing of these repeats, leading to an inversion of the NPHP1 region, followed by an interchromosomal unequal crossover event. This complex rearrangement, as well as the common deletion found in most patients, illustrates the high level of rearrangements occurring in the centromeric region of chromosome 2.

Familial juvenile nephronophthisis.

Familial juvenile nephronophthisis (NPH) is an autosomal recessive interstitial nephritis leading to terminal renal failure around puberty. Associations with extrarenal symptoms have been reported, mainly with Leber amaurosis (termed Senior-Løken syndrome). By means of linkage analysis a gene NPH1 for the purely renal form of NPH has been localized to chromosome 2. Genetic heterogeneity has been shown between NPH and Senior-Løken syndrome and also within the group of isolated NPH cases. Further characterization of the NPH1 region led to the isolation of large homozygous deletions in approximately 70% of patients with NPH. The detection of these deletions by PCR represents a simple noninvasive method for precise diagnosis in the majority of patients suspected of having NPH.

A novel gene that encodes a protein with a putative src homology 3 domain is a candidate gene for familial juvenile nephronophthisis.

Familial juvenile nephronophthisis (NPH) is an autosomal recessive, genetically heterogeneous disorder, representing the most frequent inherited cause of chronic renal failure in children. One of the responsible loci, NPH1 , has been mapped to 2q13. The presence of large homozygous deletions of approximately 250 kb in the majority of affected patients allowed us to define a minimal deletion interval for NPH1 . A BAC contig covering this interval was established. Combination of large scale genomic sequencing, cDNA selection and computer-aided analysis led to the characterization of two transcriptional units. One encodes the already known BENE protein, and the other encodes a novel protein of at least 732 amino acids containing a putative src homology 3 domain. In two patients carrying the large deletion of the NPH1 region on only one allele, two mutations were detected in two independent exons of the novel gene. One consists of a single base deletion, causing a frameshift, and the other is a G-->A substitution in the consensus 5' splice donor site. Both mutations thus potentially generate null mutants. One of these mutations was found to segregate with the disease in the family, and the second appeared to be a de novo mutation. We therefore conclude that this novel gene is a strong candidate for NPH.

Large homozygous deletions of the 2q13 region are a major cause of juvenile nephronophthisis.

Juvenile nephronophthisis (NPH) is a genetically heterogeneous disorder representing the most frequent inherited cause of chronic renal failure in children. We recently assigned a gene (NPH1) to the 2q13 region which is responsible for approximately 85% of cases. Cloning this region in a yeast artificial chromosome contig revealed the presence of low copy repeats. Large-scale rearrangements were detected in 80% of the patients belonging to inbred or multiplex NPH1 families and in 65% of the sporadic cases. Surprisingly, these rearrangements seem to be, in most cases, large homozygous deletions of approximately 250 kb involving an 100 kb inverted duplication. This suggests a common genetic disease-causing mechanism, which could be responsible for the highest frequency of large rearrangements reported in an autosomal recessive trait. Our findings are also of major clinical interest, as they permit the diagnosis in the majority of sporadic cases without the need for kidney biopsy.

[The computerized clinical record. Myth and reality]. / O processo clínico informatizado. O mito e a realidade.

The state of the art in medical informatics is presented, in science as well as in the technological field. After the inventory of the solutions provided it is postulated that informatics and medicine are inevitable partners, but it is a globally positive marriage.

Operacao cesariana em Recife em 1979: incidencia e mortalidade materna. / Cesarean section in Recife during 1979: incidence and maternal death rate

Em 19 maternidades da cidade do Recife (Pernambuco, Brasil), em 1979, houve um total de 12 156 cesarianas (incidencia de 28,1%) e 30 953 partos vaginais. A mortalidade materna na operacao cesariana, foi de 3,3 por 1 000.Nas pacientes indigentes, foram realizadas 2 327 cesarianas (incidencia de 11,2%) e 18 414 partos vaginais. A mortalidade materna na operacao cesariana foi de 9 por 1 000. Nas pacientes do INAMPS, foram realizadas 5621 cesarianas (incidencia de 35,4%) e 10226 partos vaginais. A mortalidade materna na operacao cesariana foi de 3 por 1000. Nas pacientes previdenciarias estaduais e militares, foram realizadas 444 cesarianas (incidencia de 42,6%) e 596 partos vaginais. A mortalidade materna na operacao cesariana foi de 2,2 por 1 000. Nas pacientes de clinica particular, foram realizadas 3 764 cesarianas (incidencia de 67,7%) e 1 717 partos vaginais A mortalidade materna na operacao cesariana foi de 0,5 por 1 000. As causas mais frequentes de mortalidade materna foram: hemorragia, eclampsia, infeccao e embolia amniotica. No global, a mortalidade materna na operacao cesariana foi 6,13 vezes maior do que no parto vaginal