Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS)

Background. Recessive mutations in the NPHS1 gene encoding nephrin account for ∼40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons. Methods. We here performed mutational analysis of NPHS1 in a worldwide cohort of 67 children from 62 different families with CNS. Results. We found bi-allelic mutations in 36 of the 62 families (58%) confirming in a worldwide cohort that about one-half of CNS is caused by NPHS1 mutations. In 26 families, mutations were homozygous, and in 10, they were compound heterozygous. In an additional nine patients from eight families, only one heterozygous mutation was detected. We detected 37 different mutations. Nineteen of the 37 were novel mutations (∼51.4%), including 11 missense mutations, 4 splice-site mutations, 3 nonsense mutations and 1 small deletion. In an additional patient with later manifestation, we discovered two further novel mutations, including the first one affecting a glycosylation site of nephrin. Conclusions. Our data hereby expand the spectrum of known mutations by 17.6%. Surprisingly, out of the two siblings with the homozygous novel mutation L587R in NPHS1, only one developed nephrotic syndrome before the age of 90 days, while the other one did not manifest until the age of 2 years. Both siblings also unexpectedly experienced an episode of partial remission upon steroid treatmen

Clinicopathological profile of pediatric renal biopsies at a tertiary care hospital, Pakistan

Renal biopsy is an important tool for the diagnosis of acute and chronic glomerular diseases in children. We aimed to analyze the spectrum of clinical indications and histopathological patterns (HPP) in children who underwent renal biopsy (RB). This is a retrospective review of case records of 108 renal biopsies carried out from January 2010 to December 2015 at the Pediatric Nephrology Department, National Institute of Child Health Karachi, Pakistan. RB was performed under Ketamine-Midazolam sedation and real-time ultrasound. Trucut or monopty biopsy gun was used. Data obtained included age, gender, clinical indications, biochemical, urinary, and HPP. Data analyzed by descriptive statistics using SPSS version 20. Of the total 108 patients who underwent renal biopsy, males were 56.5%. The mean age of children at biopsy and disease onset was 7.0 ± 4.28 (0. 2–17) and 5.8 ± 4.09 (0.1–15) years, respectively. Common indications for renal biopsy in primary glomerulonephritis (PGN) were steroid-resistant nephrotic syndrome (SRNS, 36.1%), steroid-dependent nephrotic syndrome (SDNS, 21.3%), and acute nephritic syndrome (ANS) with acute kidney injury (12.0%). Other indications were systemic lupus erythematosus with nephritis and Henoch-Schonlein purpura among secondary GN. Histopathological pattern in PGN showed focal segmental glomerulosclerosis (FSGS, 25.9%), minimal change disease (MCD, 22.2%), membranoproliferative GN (MPGN, 12%), and IgM nephropathy (7.4%). Lupus nephritis (7.4%) was the most common among secondary GN (SGN). Among 22 SDNS; MCD was found in 16, FSGS in four, and MPGN in two children whereas among 40 SRNS; 10 had MCD, 16 FSGS, and two had MPGN. We concluded that most common indications of renal biopsy were SRNS followed by SDNS and ANS. FSGS was the predominant HPP among SRNS and MCD among SDNS

Urolithiasis Associated Morbidity in Children

Background : To determine the various types of medical complications associated with urolithiasis in children.Methods: In this descriptive study 60 children of 1 month to 12 years age with haematuria, abdominal pain, history of passing stone or retention of urine and confirmed as suffering from renal calculi on radiological examination were selected. Initial investigations included urine routine examination, culture and sensitivity, blood urea, serum creatinine, serum electrolytes, plain x-ray Kidney, Ureter and Bladder and ultrasound for KUB. Further investigation like IVP, MCUG, nuclear scans such as DTPA, DMSA , MAG3 and metabolic screening for stones were done where required.Results: Majority (66%) were boys, with male: female ratio 2:1. Acute renal failure was present in 33% of the patients, and urinary tract infections in 23% of the patients. Many patients had more than one complication. Calculus anuria was seen in 3(5%) patients. Hypertension and urosepsis were observed in 1.6%, each. Fifteen patients had calcium stones and six patients had oxalate stonesConclusion: Acute renal failure is the most common renal complication which can be prevented with early diagnosis and management

Infantile Spasms: Clinical profile and treatment outcomes

Background and Objective: Infantile spasm (IS) is one of the severe epileptic encephalopathies which affect children in early two years of life. Our objective was to determine the clinical profile, etiology and outcome of treatment in children with infantile spasms attending tertiary care hospital at Karachi, Pakistan. Methods: This is retrospective study of 36 patients out of 94 registered as IS, aged three months to two years, managed and followed up at Aga Khan University Hospital, Karachi, from 2010 to 2015. Data of all children with IS was collected from case record. Details including clinical observations, lab investigations, anti-epileptic medications and treatment outcome was collected and analyzed. Patients who received treatment for six weeks to document response were included. The treatment response was categorized as complete response, partial response (\u3e50% improvement) and no response. Data was analyzed on SPSS using descriptive statistics. Results: Thirty-six patients (38.29%) with IS fulfilled eligibility criteria. The mean ± SD age at presentation was 4.6±2.1 months. Male to female ratio was 2:1. Consanguinity and developmental motor delay was observed in 66.6% and 89% respectively. Symptomatic etiology was predominant (61%) and hypoxic ischemic insult (32%) was the commonest underlying cause. EEG and MRI were diagnostic tools whereas metabolic studies were not helpful. Multiple antiepileptic drugs were used for seizure control and vigabatrin was the most frequently used (88%) drug. Short term treatment response was not different in idiopathic or symptomatic infantile spasms. Conclusion: Majority of patients had symptomatic infantile spasms and generalized tonic clonic along with myoclonic jerks were predominant seizure types. EEG and MRI were diagnostic in most of cases. Multiple AEDs were required to control seizures and VGB was most common drug (88%) used. Treatment outcome was not different in idiopathic and symptomatic groups

Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS)

Background. Recessive mutations in the NPHS1 gene encoding nephrin account for ∼40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons

Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity

Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we, performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIASI, INCENP, and RCORI) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes

Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A