Genetic basis of Bartter syndrome in Korea BEOM HEE LEE; HEE YEON CHO; KIM, Su-Yung ...
Nephrology, dialysis, transplantation,
04/2012, Letnik:
27, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Bartter syndrome (BS) is clinically classified into antenatal or neonatal BS (aBS) and classic BS (cBS) as well as five subtypes based on the underlying mutant gene; SLC12A1 (BS I), KCNJ1 (BS II), ...CLCNKB (BS III), BSND (BS IV) and CASR (BS V).
Clinico-genetic features of a nationwide cohort of 26 Korean children with BS were investigated.
The clinical diagnosis was aBS in 8 (30.8%), cBS in 15 (57.7%) and mixed Bartter-Gitelman phenotype in 3 cases (11.5%). Five of eight patients with aBS and all 18 patients with either cBS or mixed Bartter-Gitelman phenotype had CLCNKB mutations. Among the 23 patients (46 alleles) with CLCNKB mutations, p.W610X and large deletions were detected in 25 (54.3%) and 10 (21.7%) alleles, respectively. There was no genotype-phenotype correlation in patients with CLCNKB mutations.
Twenty-three (88.5%) of the 26 BS patients involved in this study had CLCNKB mutations. The p.W610X mutation and large deletion were two common types of mutations in CLCNKB. The clinical manifestations of BS III were heterogeneous without a genotype-phenotype correlation, typically manifesting cBS phenotype but also aBS or mixed Bartter-Gitelman phenotypes. The molecular diagnostic steps for patients with BS in our population should be designed taking these peculiar genotype distributions into consideration, and a new more clinically relevant classification including BS and Gitelman syndrome is required.
This study investigated whether the promoter region of DNA methylation positively or negatively regulates tissue-specific genes (TSGs) and if it correlates with disease pathophysiology. We assessed ...tissue specificity metrics in five human tissues, using sequencing-based approaches, including 52 whole genome bisulfite sequencing (WGBS), 52 RNA-seq, and 144 chromatin immunoprecipitation sequencing (ChIP-seq) data. A correlation analysis was performed between the gene expression and DNA methylation levels of the TSG promoter region. The TSG enrichment analyses were conducted in the gene-disease association network (DisGeNET). The epigenomic association analyses of CpGs in enriched TSG promoters were performed using 1986 Infinium MethylationEPIC array data. A correlation analysis showed significant associations between the promoter methylation and 449 TSGs' expression. A disease enrichment analysis showed that diabetes- and obesity-related diseases were high-ranked. In an epigenomic association analysis based on obesity, 62 CpGs showed statistical significance. Among them, three obesity-related CpGs were newly identified and replicated with statistical significance in independent data. In particular, a CpG (cg17075888 of
), considered as potential therapeutic targets, were associated with complex diseases, including obesity and type 2 diabetes. The methylation changes in a substantial number of the TSG promoters showed a significant association with metabolic diseases. Collectively, our findings provided strong evidence of the relationship between tissue-specific patterns of epigenetic changes and metabolic diseases.
Purpose: Chronic kidney disease (CKD) has various underlying causes in children. Identification of the underlying causes of CKD is important. Genetic causes comprise a significant proportion of ...pediatric CKD cases.Methods: In this study, we performed whole-exome sequencing (WES) to identify genetic causes of pediatric CKD. From January to June 2021, WES was performed using samples from pediatric patients with CKD of unclear etiology. Results: Genetic causes were investigated using WES in 37 patients (17 males) with pediatric CKD stages 1 (n=5), 2 (n=7), 3 (n=2), 4 (n=2), and 5 (n=21). The underlying diseases were focal segmental glomerulosclerosis (n=9), congenital anomalies of the kidney and urinary tract including reflux nephropathy (n=8), other glomerulopathies (n=7), unknown etiology (n=6), and others (n=7). WES identified genetic causes of CKD in 12 of the 37 patients (32.4%). Genetic defects were discovered in the COL4A4 (n=2), WT1 (n=2), ACTN4, CEP290, COL4A3, CUBN, GATA3, LAMA5, NUP107, and PAX2 genes. WT1 defects were found in patients whose pathologic diagnosis was membranoproliferative glomerulonephritis, and identification of CUBN defects led to discontinuation of immunosuppressive agents. Genetic diagnosis confirmed the clinical diagnosis of hypoparathyroidism, sensorineural deafness, and renal disease; Alport syndrome; and Joubert syndrome in three of the patients with CKD of unknown etiology (COL4A4 n=2, CUBN n=1). Extrarenal symptoms were considered phenotypic presentations of WT1, PAX2, and CEP290 defects.Conclusions: WES provided a genetic diagnosis that confirmed the clinical diagnosis in a significant proportion (32.4%) of patients with pediatric CKD.
HNF1B mutations, one of the most common causes of congenital anomalies of the kidney and urinary tract, manifest as various renal and extrarenal phenotypes. We analyzed the genotype-phenotype ...correlations in 14 pediatric patients with HNF1B mutations. Genetic studies revealed total gene deletion in six patients (43%). All patients had bilateral renal abnormalities, primarily multiple renal cysts. Twelve patients exhibited progressive renal functional deterioration, and six of them progressed to kidney failure. The annual reduction in estimated glomerular filtration rate was−2.1 mL/min/1.73 m2. Diabetes developed in five patients (36%), including one patient with new-onset diabetes after transplantation. Neurological deficits were noted in three patients (21%), one with total gene deletion and two with missense mutations. Pancreatic abnormalities were more frequent in patients with missense mutations than in patients with other types of mutations. Genotype showed no significant correlation with renal outcomes or other extrarenal manifestations. The HNF1B scores at the times of onset and genetic diagnosis were <8 in two patients and one patient, respectively. Diagnosis of HNF1B mutations is clinically difficult because of extreme phenotypic variability and incomplete penetrance. Furthermore, some phenotypes develop with age. Therefore, patient age should be taken into consideration to increase the diagnostic rate, because some phenotypes develop with age.
Hematuria is the presence of blood in the urine and is classified as either gross hematuria or microscopic hematuria. There are many causes of hematuria, and the differential diagnosis depends on the ...presence or absence of comorbidities and whether it is glomerular or non-glomerular. When hematuria in children is symptomatic or persistent, an evaluation of the cause is essential. The causes of hematuria and basic approaches to its diagnosis are discussed in this review.
Galloway-Mowat syndrome (GAMOS) is a rare hereditary renal-neurological disease characterized by early-onset steroid-resistant nephrotic syndrome in combination with microcephaly and brain anomalies. ...Recently, novel causative mutations for this disease have been identified in the genes encoding the four KEOPS subunits: OSGEP, TP53RK, TPRKB, and LAGE3.
We detected a novel homozygous TP53RK mutation (NM_033550, c.194A > T, p.Lys65Met) using whole exome sequencing in a familial case of GAMOS with three affected siblings. All three patients manifested similar phenotypes, including very early-onset nephrotic syndrome (8 days, 1 day, and 1 day after birth, respectively), microcephaly, dysmorphic faces, and early fatality (10 months, 21 days, and 25 days of age, respectively). One patient also showed hiatal hernia with gastric volvulus. Renal biopsy performed on one patient revealed focal segmental glomerulosclerosis with severe tubulo-interstitial changes.
We report on a familial case of GAMOS with three affected siblings carrying a novel homozygous TP53RK mutation. To our knowledge, this is only the second report on GAMOS in association with a TP53RK mutation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Acute kidney injury (AKI) is a critical issue in cancer patients because it is not only a morbid complication but also able to interrupt timely diagnostic evaluation or planned optimal ...treatment. However, the impact of AKI on overall mortality in cancer patients remains unclear.
Methods
We conducted a retrospective cohort study of 67 986 cancer patients, from 2004 to 2013 to evaluate the relationship between AKI and all‐cause mortality. We used KDIGO AKI definition and grading system.
Results
During 3.9 ± 3.1 years of follow‐up, 33.8% of the patients experienced AKI at least once. Among AKI events, stage 1, 2, and 3 was 71.0%, 13.8%, and 15.1%, respectively. AKI incidence was highest in hematologic malignancies, followed by urinary tract cancer, and hepatocellular carcinoma. Male sex, older age, underlying diabetes and hypertension, lower serum albumin and plasma hemoglobin, more frequent radio‐contrast exposure, entrance of clinical trials, and receiving chemotherapy were associated with AKI occurrence. AKI development was an independent risk factor for elevated mortality in cancer patients with dose‐responsive manner (Stage 1, hazard ratio HR 1.183, 95% confidence interval CI 1.145‐1.221, P < 0.001; Stage 2, HR 1.710, 95% CI 1.629‐1.796; Stage 3, HR 2.000, 95% CI 1.910‐2.095; No AKI, reference group) even after adjustment. This tendency was reproduced in various cancer types except thyroid cancer and in various treatment modalities, however, not shown in patients with baseline renal dysfunction.
Conclusion
AKI was an independent risk factor for all‐cause mortality in overall cancer patients with dose‐responsive manner.
Acute kidney injury (AKI) is a critical issue in cancer patients because it is not only a morbid complication but also able to interrupt timely diagnostic evaluation or planned optimal treatment. In this study, AKI was an independent risk factor for all‐cause mortality in overall cancer patients with dose‐responsive manner.
Atypical progeroid syndrome (APS) is a rare type of progeroid syndrome mainly caused by heterozygous missense mutations in the
LMNA
(MIM 150330) gene. APS has heterogeneous clinical manifestations, ...and its kidney manifestations, particularly in children, are rarely documented. Here, we report the first pediatric case of APS with focal segmental glomerulosclerosis (FSGS). A 10-year-old boy with progeroid features was referred to the nephrology clinic because of hyperuricemia. He had dark skin, protruding eyes, and beaked nose and was very thin, suggesting lipodystrophy. He had been treated for recurrent urinary tract infection during infancy, and liver biopsy for persisting hepatitis showed steatohepatitis. He also had hypertrophic cardiomyopathy (HCMP) with mitral and tricuspid valve regurgitation. Genetic studies were performed considering his multisystem symptoms, and he was diagnosed as having APS according to exome sequencing findings (c.898G > C,
p
.Asp300His of
LMNA
). During the first visit to the nephrology clinic, he had minimal proteinuria (urine protein/creatinine ratio of 0.23 mg/mg), which worsened during follow-up. In three years, his urine protein/creatinine ratio and N-acetyl-b-D-glucosaminidase/creatinine ratio increased to 1.52 and 18.7, respectively. The kidney biopsy result was consistent with findings of FSGS, peri-hilar type, showing segmental sclerosis of 1 (5%) glomerulus out of 21 glomeruli. An angiotensin receptor blocker was added to manage his proteinuria. This is the first pediatric report of FSGS in an APS patient with confirmed
LMNA
defect, who manifested progeroid features, lipodystrophy, HCMP with heart valve dysfunction, and steatohepatitis. Our case suggests that screening for proteinuric nephropathy is essential for managing APS patients since childhood.
Children with chronic kidney disease (CKD) have a high risk of cardiovascular disease. Left-ventricular (LV) hypertrophy (LVH) is an early marker of cardiovascular disease in pediatric CKD, and the ...prevalence of LVH in pediatric CKD is approximately 20-30% in pre-dialysis CKD patients. However, there is no consensus on the ideal method of defining LVH in pediatric CKD patients. Previous studies have typically used the LV mass index (LVMI), which is calculated as LV mass in grams divided by height in meters to the 2.7th power ≥ 38 g/m2.7, to diagnose LVH in children with CKD. Recently, age-specific reference values for LVMI ≥ 95th percentile and LV wall-thickness z-score > 1.64 in children were addressed. The aim of this study was to assess the prevalence and contributing factors of LVH in pediatric CKD patients according to each measurement and evaluate the concordance between each measurement.
We used the baseline data of the KoreaN cohort study for Outcome in patients With Pediatric Chronic Kidney Disease (KNOW-Ped CKD), which is a nationwide, 10-year, prospective, observational cohort study of pediatric CKD. A total of 469 patients were enrolled, and 458 patients were included in the final analysis. Univariate and multiple logistic regression analysis were performed to evaluate the association of the variables with LVH. Kappa statistics were used to analyze the concordance.
According to an LVH diagnosis of LVMI ≥ 38 g/m2.7, 188 patients (41.0%) were diagnosed with LVH, and the prevalence of LVH was high in younger patients (< 2 years of age). Using the age-specific reference values, 116 patients (25.3%) were diagnosed with LVH, and there was no difference in the prevalence of LVH according to age. Thirty-one patients (6.8%) were diagnosed with LVH using an LV wall-thickness z-score > 1.64. There is poor concordance between the diagnosis of LVH using the LV wall-thickness z-score and the LVMI method.
The results of this study show that there is poor concordance between the diagnosis of LVH using the wall-thickness z-score and the LVMI2.7 criteria. Further investigation is needed to estimate the correlation between LVH and cardiac dysfunction and to find a better method for defining LVH in the pediatric CKD cohort and thereby predicting cardiac dysfunction.
Renovascular hypertension (RVHT) is an important cause of childhood hypertension. This study evaluated the clinical characteristics and outcomes of Korean children with RVHT.
Children treated for ...RVHT between 2000 and 2015 at our center were retrospectively reviewed.
Forty-six children were followed for a median of 6.5 (0.66-27.23) years. Forty-five percutaneous transluminal angioplasties (PTAs) were performed in 32 children. At the last visit, clinical benefit was observed in 53.3% of children. Patients with comorbid cerebrovascular disease (CVD) showed less favorable long-term outcomes after PTA (clinical benefit in 41.7% vs. 61.1% in others) and higher restenosis rates (50% vs. 31.6% in others). Surgical procedures (bypass or nephrectomy) were performed in 8 patients. After surgery, blood pressure was normalized in 2 patients, improved in 3 patients, and unchanged in the remaining patients. Between PTA group (n=21) and medication group (n=14), percentage of atrophic kidneys became higher after follow-up period in medication group than in PTA group (60.0% vs. 26.1%, P=0.037).
Aggressive treatment of pediatric RVHT yielded fair outcomes in our cohort. CVD comorbidity was associated with relatively poor PTA outcomes. To confirm our findings, larger cohort studies with a longer follow-up period are warranted.
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