Expanding the spectrum of EEF1D neurodevelopmental disorders: Biallelic variants in the guanine exchange domain.

Protein translation is an essential cellular process and dysfunctional protein translation causes various neurodevelopmental disorders. The eukaryotic translation elongation factor 1A (eEF1A) delivers aminoacyl-tRNA to the ribosome, while the eEF1B complex acts as a guanine exchange factor (GEF) of GTP for GDP indirectly catalyzing the release of eEF1A from the ribosome. The gene EEF1D encodes the eEF1Bδ subunit of the eEF1B complex. EEF1D is alternatively spliced giving rise to one long and three short isoforms. Two different homozygous, truncating variants in EEF1D had been associated with severe intellectual disability and microcephaly in two families. The published variants only affect the long isoform of EEF1D that acts as a transcription factor of heat shock element proteins. By exome sequencing, we identified two different homozygous variants in EEF1D in two families with severe developmental delay, severe microcephaly, spasticity, and failure to thrive with optic atrophy, poor feeding, and recurrent aspiration pneumonia. The EEF1D variants reported in this study are localized in the C-terminal GEF domain, suggesting that a disturbed protein translation machinery might contribute to the neurodevelopmental phenotype. Pathogenic variants localized in both the alternatively spliced domain or the GEF domain of EEF1D cause a severe neurodevelopmental disorder with microcephaly and spasticity.

Presentation of pediatric Henoch-Schönlein purpura nephritis changes with age and renal histology depends on biopsy timing.

BACKGROUND: This study correlates the clinical presentation of Henoch-Schönlein purpura nephritis (HSPN) with findings on initial renal biopsy. METHODS: Data from 202 pediatric patients enrolled in the HSPN registry of the German Society of Pediatric Nephrology reported by 26 centers between 2008 and 2014 were analyzed. All biopsy reports were re-evaluated for the presence of cellular crescents or chronic pathological lesions (fibrous crescents, glomerular sclerosis, tubular atrophy >5%, and interstitial fibrosis >5%). RESULTS: Patients with HSPN with cellular glomerular crescents were biopsied earlier after onset of nephritis (median 24 vs 36 days, p = 0.04) than those without, whereas patients with chronic lesions were biopsied later (57 vs 19 days, p < 0.001) and were older (10.3 vs 8.6 years, p = 0.01) than those without. Patients biopsied more than 30 days after the onset of HSPN had significantly more chronic lesions (52 vs 22%, p < 0.001), lower eGFR (88 vs 102 ml/min/1.73m2, p = 0.01), but lower proteinuria (2.3 vs 4.5 g/g, p < 0.0001) than patients biopsied earlier. Children above 10 years of age had lower proteinuria (1.98 vs 4.58 g/g, p < 0.001), lower eGFR (86 vs 101 ml/min/1.73m2, p = 0.002) and were biopsied significantly later after onset of nephritis (44 vs 22 days, p < 0.001) showing more chronic lesions (45 vs 30%, p = 0.03). Proteinuria and renal function at presentation decreased with age. CONCLUSIONS: In summary, we find an age-dependent presentation of HSPN with a more insidious onset of non-nephrotic proteinuria, impaired renal function, longer delay to biopsy, and more chronic histopathological lesions in children above the age of 10 years. Thus, HSPN presents more like Immunoglobulin A (IgA) nephritis in older than in younger children.

FAT1 mutations cause a glomerulotubular nephropathy.

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.

Non-invasive ventilation on a pediatric intensive care unit: feasibility, efficacy, and predictors of success.

BACKGROUND: There is only sparse data on the use of non-invasive ventilation (NIV) in acute respiratory failure (ARF) in infants and children. For this setting we investigated feasibility and efficacy of NIV and aimed to identify early predictors for treatment failure. PATIENTS AND METHODS: Retrospective chart review was performed for all patients treated with NIV for ARF from 2003 to 2010 on an 8-bed pediatric intensive care unit of a tertiary university hospital. RESULTS: Seventy-four patients were treated with NIV. One patient did not tolerate mask ventilation and needed immediate invasive ventilation. Intubation rate of the remaining patients was 23% and mortality 15%. Institution of NIV led to significant improvement of both respiratory and heart rate in all patients within the first hour and to further stabilization within the next 8-10 hr. In patients with NIV success blood gases improved significantly 1-2 hr after starting NIV. Multivariate analysis identified low pH after 1-2 hr to be an individual risk factor for NIV failure. Other factors tested were age, underlying disease, acute respiratory insufficiency versus post-extubation failure (PEF), and 1-2 hr after starting NIV oxygen saturation, respiratory rate, PCO(2) , and FiO(2) . Patients with PEF tended to show better outcomes compared to those with acute respiratory insufficiency. CONCLUSION: NIV can be effective in infants and children with ARF. Low pH 1-2 hr after start of NIV is associated with NIV failure. It may therefore be useful in the decision to continue or stop mask ventilation.

Paediatric acute liver failure and transplantation: the University of Essen experience.

To report our experience with 17 children who underwent a liver transplantation (LT) for acute liver failure (ALF). All LT procedures (deceased and living donor) were offered. Since 2003 Molecular Adsorbents Recycling System (MARS) was proposed as bridging procedure. We monitored the perioperative course and the short- and long-term outcomes. All children developed pretransplant hepatic encephalopathy (mostly grades II and III); six needed ventilator support and three haemodialysis. Median PELD/MELD score was 30. MARS was used in five children with poor pretransplant prognostic factors: all five survived the LT without sequelae. We performed 13 deceased donor LT (seven whole, five split and onr reduced) and four left lateral LDLT. Postoperative complications were observed in 10 children, requiring re-operation in seven. Two children developed irreversible neurological disorders. After a median follow up of 45 months, 16 children are still alive. About 1- and 5-year cumulative patient survival rates are 94% with a corresponding graft survival of 88% and 81%, respectively. The combination of experienced paediatric ICU management, the application of new liver support devices, and the capacity to offer both living and deceased donor transplant alternatives in a timely fashion represent the best formula to achieve optimal results in children with ALF.

CNS or bone marrow involvement as risk factors for poor survival in post-transplantation lymphoproliferative disorders in children after solid organ transplantation.

PURPOSE: To identify prognostic factors of survival in pediatric post-transplantation lymphoproliferative disorder (PTLD) after solid organ transplantation. PATIENTS AND METHODS: A multicenter, retrospective case analysis of 55 pediatric solid organ graft recipients (kidney, liver, heart/lung) developing PTLD were reported to the German Pediatric-PTLD registry. Patient charts were analyzed for tumor characteristics (histology, immunophenotypes, cytogenetics, Epstein-Barr virus [EBV] detection), stage, treatment, and outcome. Probability of overall and event-free survival was analyzed in defined subgroups using univariate and Cox regression analyses. RESULTS: PTLD was diagnosed at a median time of 29 months after organ transplantation, with a significantly shorter lag time in liver (0.83 years) versus heart or renal graft recipients (3.33 and 3.10 years, respectively; P = .001). The 5-year overall and event-free survival was 68% and 59%, respectively, with 59% of patients surviving 10 years. Stage IV disease with bone marrow and/or CNS involvement was associated independently with poor survival (P = .0005). No differences in outcome were observed between early- and late-onset PTLD, monomorphic or polymorphic PTLD, and EBV-positive or EBV-negative PTLD, respectively. Patients with Burkitt or Burkitt-like PTLD and c-myc translocations had short survival (< 1 year). CONCLUSION: Stage IV disease is an independent risk factor for poor survival in pediatric PTLD patients. Prospective multicenter trials are needed to delineate additional risk factors and to assess treatment approaches for pediatric PTLD.

Removal of metabolites, cytokines and hepatic growth factors by extracorporeal liver support in children.

BACKGROUND: Molecular Adsorbents Recirculating System (MARS)-mini has recently been approved and applied in children with hepatic failure. However, its indication, efficacy and capability to induce liver regeneration remain unclear. The aim of our pilot study in children was to analyse the impact of MARS on markers of detoxification and regeneration. METHODS: In children with fulminant Wilson's disease and bridged with MARSmini for liver transplantation, we analyzed toxic metabolites (bile acids, bilirubin, lactate, ammonia, tryptophan and copper), regulators of the inflammatory cascade [nitrate, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), methionine, cystine and hyaluronic acid] and hepatic growth factors [hepatocyte growth factor (HGF), epidermal growth factor (EGF), transforming growth factor-beta1 (TGF-beta1), cortisol, corticosteroid-binding globulin (CBG), insulin-like growth factor-1 (IGF-1), angiogenin, vascular endothelial growth factor (VEGF), IL-6 and TNF-alpha] from blood, albumin circuit and haemodialysate from four applications. RESULTS: In all four applications, transfer of toxic metabolites (6/6) and inflammatory mediators (6/6), but also of hepatic growth factors (9/10), into the albumin circuit of MARS was consistently detected. Corresponding blood levels were decreased for 3/6 metabolites, 3/6 inflammatory mediators and 1/10 growth factors and increased for 1/10 growth factors. Bridging for liver transplantation was successful with MARS. CONCLUSIONS: In our prospective study, substantial extraction of albumin-bound and water-soluble candidate substances was detected with variable effect on respective blood levels. Notably, essential factors inducing liver regeneration were simultaneously removed. These data provide a basis for evaluation of liver restoration and efficacy of liver support in children with liver failure to devise a collaborative, multicentre trial.

Long-term survival and late graft loss in pediatric liver transplant recipients--a 15-year single-center experience.

Increasing numbers of children undergo successful liver transplantation. Limited data exist on long-term survival and late graft loss. Survival and graft loss were studied in 376 primary liver graft recipients who survived more than 3 months after transplantation (80.5% of all primary graft recipients). Patient records were reviewed retrospectively for causes of graft loss. Risk factors were identified by analyzing graft, recipient, and posttransplant variables using multivariate Cox regression. One-, 5-, and 10-year actuarial graft survival rates in the study population were 94.6%, 87.3%, and 86.3%, respectively. Corresponding patient survival rates were 95.7%, 91.4%, and 90.4%. Forty-seven (12.5%) grafts were lost subsequently, 15 by patient death with preserved graft function. Survival rate after late retransplantation was 63.3%. Causes of late graft loss were infection (21.2%), posttransplant lymphoproliferative disease (PTLD, 21.2%), chronic rejection (17%), biliary complications (14.8%), and recurrence of malignant disease (8.5%). Independent risk factors for late graft loss and patient death included liver malignancy as primary disease, steroid resistant rejection, and PTLD. Graft loss rate was significantly increased for reduced-size grafts. Patients undergoing transplantation after 1991 and recipients of full-size grafts were more likely to survive. In conclusion, the long-term outcome for pediatric primary liver graft recipients surviving the early postoperative period is excellent except for patients with liver malignancy. There is no increased risk of late graft loss with the use of split or living related donor grafts. Technical complications are only a minor factor in late graft loss, but complications related to immunosuppression and infection remain a major hazard and must be addressed.

Repeated detection of gas in the portal vein after liver transplantation: A sign of EBV-associated post-transplant lymphoproliferation?

A 1-yr-old child presented with intractable right sided pleural effusion and progressive clinical deterioration 3 weeks after liver transplantation for Alagille Syndrome. He had been treated successfully for severe acute rejection before. Ultrasound and Doppler mode studies repeatedly demonstrated air in the portal vein. Intra-abdominal and intra-thoracic lymphoproliferation was detected, and EBV virus load and serology were suggestive of primary EBV infection. Liver biopsy revealed blast-like infiltrates of B-cells, considered diagnostic for post-transplant lymphoproliferative disease. The disease resolved upon reduction of immunosuppression. We suggest that the detection of portal vein gas in pediatric liver transplant recipients beyond the early post-operative period may be a sign of intra-abdominal post-transplant lymphoproliferative disease.