Angiotensin type 2 receptor gene null mutant mice display congenital anomalies of the kidney and urinary tract (CAKUT). Various features of mouse CAKUT impressively mimic human CAKUT. Studies of the human type 2 receptor (AGTR2) gene in two independent cohorts found that a significant association exists between CAKUT and a nucleotide transition within the lariat branchpoint motif of intron 1, which perturbs AGTR2 mRNA splicing efficiency. AGTR2, therefore, has a significant ontogenic role for the kidney and urinary tract system. Studies revealed that the establishment of CAKUT is preceded by delayed apoptosis of undifferentiated mesenchymal cells surrounding the urinary tract during key ontogenic events, from the ureteral budding to the expansive growth of the kidney and ureter.

Objective: Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. The study was conducted to assess the impact of early detection of SMA by newborn screening (NBS) on the clinical course of the disease. Methods: Screening was performed in two federal states of Germany, Bavaria and North Rhine Westphalia, between January 2018 and February 2019. The incidence in the screening population was calculated as number of detected patients with a homozygous deletion in the SMN1-gene per number of screened patients. To get an idea about the incidence of newly diagnosed SMA in the year prior to screening a survey covering all neuropediatric centers in the state of Bavaria was conducted, identifying all SMA-cases in 2017 and 2018. Following positive NBS and confirmatory diagnostic test, treatment was advised according to the recommendations of the "American SMA NBS Multidisciplinary Working Group". Immediate treatment with Nusinersen was recommended in children with 2 and 3 SMN2 copies and a conservative strict follow-up strategy in children with ≥4 copies. All children underwent regular standardized neuropediatric examination, CHOP INTEND and HINE-2 testing as well as electrophysiological exams every 2-3 months. Results: 165,525 children were screened. 22 cases of SMA were identified, meaning an incidence rate of 1:7524. SMN2 copy number analysis showed 2 SMN2 copies in 45% of patients, 3 SMN2 copies in 19 % and 4 SMN2 copies in 36%. These

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We investigated angiotensin converting enzyme gene (ACE I/D) polymorphism as a risk for progressive renal damage in congenital uropathies. The ACE I/D genotype was determined in 196 Caucasian patients with congenital uropathies and 163 individuals with no clinical or sonographic evidence of any urological malformations. The study group included patients with ureteropelvic junction obstruction (n=49), primary obstructive megaureter (n=19), primary vesicoureteral reflux (VUR) (n=67), and posterior urethral valves (n=27). Thirty-four patients were excluded because of additional diseases or insufficient follow-up. There was no difference in the ACE I/D distribution between children with uropathies and normal controls (II 16%, ID 56%. DD 28% vs. II 26%, ID 50%, DD 24%). Renal lesions were found in 99 of 162 children by ultrasonography, intravenous pyelography, and nuclear scans. In these children there was significant over-representation of the DD genotype (II 11%, ID 53%, DD 36%) compared with normals (P<0.005, X2=14.9) or with patients with uropathies but no renal lesions (II 23%, ID 62%, DD 15%, P<0.005, X2=14.9). Because ACE I/D has been linked with progressive deterioration of renal function, we evaluated a subset of patients with initially normal kidneys who developed radiographic renal lesions (n=28). Among these patients there was an even greater over-representation of the DD genotype (II 0%, ID 43%, DD 57%, P<0.001, X2=22.6) compared with patients with uropathies but no radiographic lesions. Multivariate analysis revealed that the DD genotype is a risk factor for parenchymal destruction, which was independent of time of diagnosis, surgical intervention, or urinary tract infection. This finding was particularly relevant in patients with VUR who constituted the majority with initially normal kidneys who developed radiographic damage (22/28). Indeed, the odds ratio of developing parenchymal damage with VUR was significantly increased if the individual had the DD genotype (4.2, 95% confidence interval 1.4-13.0). In conclusion the ACE I/D gene polymorphism is a risk factor for renal parenchymal damage in patients with congenital urological abnormalities and appears particularly relevant in children with VUR, where it is an independent predisposing factor.