Recessive CHRM5 variant as a potential cause of neurogenic bladder.

Neurogenic bladder is caused by disruption of neuronal pathways regulating bladder relaxation and contraction. In severe cases, neurogenic bladder can lead to vesicoureteral reflux, hydroureter, and chronic kidney disease. These complications overlap with manifestations of congenital anomalies of the kidney and urinary tract (CAKUT). To identify novel monogenic causes of neurogenic bladder, we applied exome sequencing (ES) to our cohort of families with CAKUT. By ES, we have identified a homozygous missense variant (p.Gln184Arg) in CHRM5 (cholinergic receptor, muscarinic, 5) in a patient with neurogenic bladder and secondary complications of CAKUT. CHRM5 codes for a seven transmembrane-spanning G-protein-coupled muscarinic acetylcholine receptor. CHRM5 is shown to be expressed in murine and human bladder walls and is reported to cause bladder overactivity in Chrm5 knockout mice. We investigated CHRM5 as a potential novel candidate gene for neurogenic bladder with secondary complications of CAKUT. CHRM5 is similar to the cholinergic bladder neuron receptor CHRNA3, which Mann et al. published as the first monogenic cause of neurogenic bladder. However, functional in vitro studies did not reveal evidence to strengthen the status as a candidate gene. Discovering additional families with CHRM5 variants could help to further assess the genes' candidate status.

Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome.

BACKGROUND: Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance. METHODS: In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls. RESULTS: The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10-43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10-17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6. CONCLUSIONS: Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

Is mitrofanoff a more socially accepted clean intermittent catheterization (CIC) route for children and their families?

AIM: We aimed to examine the social impact of clean intermittent catheterization (CIC) on children with a neurogenic bladder and to compare the impact of urethral CIC with Mitrofanoff catheterization. METHODS: Questionnaires containing 29 questions about the social impact of CIC on the children and their families were administered with their parents or caregivers of 50 children (34 boys and 16 girls) using CIC. The mean (standard deviation [SD]) age of the children was 9.6 (4.32) years and duration on CIC was 6.1 (3.97) years. RESULTS: Seventeen children were using Mitrofanoff catheterization (group I) and 33 children urethral catheterization (group II). Of the respondents, 54% respondents reported that their children accept the use of CIC, 30% respondents reported that they do not like it, and 16% respondents reported that they always refuse and resist it. There was no difference in the level of acceptance between the two groups. Both groups reported that children were social (90%) and had close friends (88%). However, 50% felt that CIC affected mood, with 30% of the children displaying bad temper. Mitrofanoff catheterization was associated with fewer episodes of frequent urinary tract infection (p = 0.004) and greater adherence. All children from group I, who were older than 6 years, were attending school compared with 78% from group II. School performance was significantly better in group I (p = 0.022). CONCLUSION: There was acceptance of CIC by most children but Mitrofanoff catheterization seemed to have a lower social impact in terms of school performance, adherence to therapy, and complications.

Vitamin D insufficiency and treatment with oral vitamin D3 in children with chronic kidney disease.

OBJECTIVE: To investigate the effects of oral cholecalciferol on the levels of vitamin D3 and intact parathyroid hormone (iPTH) in children with chronic kidney disease (CKD). METHODS: We conducted a prospective uncontrolled observational study at the Pediatric Nephrology Clinic of King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia between January and October 2011 to assess serum 25-hydroxyvitamin D3 (25[OH]D) and iPTH in children with CKD stages 2-5. Children with low vitamin D3 levels were commenced on cholecalciferol, 2000 IU/day. Their 25(OH)D3 and iPTH levels were reassessed, first after 3 months, and then after 6 months. Data analysis was performed using the Statistical Package for Social Sciences. Paired t-test was used to compare results before and after treatment. RESULTS: Forty-five children (31 boys and 14 girls) were included in the study. Their mean+/-SD age was 9.6 +/- 4.6 years. There was significant improvement in 25(OH)D3 after 3 months (14.2 +/- 8.2 - 20 +/- 11.1 ng/mL) (p<0.001). However, only 5 children reached levels >/=30 ng/mL. There was no further improvement after 6 months of treatment (20.17 +/- 13.4 ng/mL) (p=0.65). There was no improvement in iPTH levels after 3 and 6 months. No changes were also observed in the levels of calcium, phosphate, alkaline phosphatase, or creatinine. CONCLUSION: The administration of oral vitamin D3 at 2000 IU/day resulted in significant improvement of vitamin D levels in children with CKD, but normalized only in 11% of the patients. The treatment had no effect on iPTH levels.