SCYL1 disease and liver transplantation diagnosed by reanalysis of exome sequencing and deletion/duplication analysis of SCYL1

SCYL1 disease results from biallelic pathogenic variants in SCYL1. We report two new patients with severe hepatic phenotype requiring liver transplantation. Patient charts reviewed. DNA samples and skin fibroblasts were utilized. Literature was reviewed. 13-year-old boy and 9-year-old girl siblings had acute liver insufficiency and underwent living related donor liver transplantation in infancy with no genetic diagnosis. Both had tremor, global developmental delay, and cognitive dysfunction during their follow-up in the medical genetic clinic for diagnostic investigations after their liver transplantation. Exome sequencing identified a likely pathogenic variant (c.399delC; p.Asn133Lysfs*136) in SCYL1. Deletion/duplication analysis of SCYL1 identified deletions of exons 7–8 in Patient 1. Both variants were confirmed in Patient 2 and the diagnosis of SCYL1 disease was confirmed in both patients at the age of 13 and 9 years, respectively. SCYL1 protein was not expressed in both patients' fibroblast using western blot analysis. Sixteen patients with SCYL1 disease reported in the literature. Liver phenotype (n = 16), neurological phenotype (n = 13) and skeletal phenotype (n = 11) were present. Both siblings required liver transplantation in infancy and had variable phenotypes. Exome sequencing may miss the diagnosis and phenotyping of patients can help to diagnose patients

Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling.This research was funded by Jubiläumsfonds der Österreichischen Nationalbank, grant no.16678 (to A.R.J.), grant no. 18019 (to G.-F.V.) and Tiroler Wissenschaftsfonds, grant No. 0404/2386 (toG.-F.V.).info:eu-repo/semantics/publishedVersio

The efficacy of a novel peristaltic feeding tube (PFT) in reducing reflux and aspiration of gastric contents in mechanically ventilated patients

Summary: Gastro-esophageal reflux (GER) is common in ventilated patients and is a cause of ventilator associated pneumonia (VAP). The novel persistaltic feeding tube (PFT) uses simulated peristalsis to seal the esophagus to fluid moving in a retrograde manner, whilst allowing normal drainage of fluid and secretions moving in an ante-grade manner. This study describes the first trial of the PFT in ventilated patients. Methods: There were 10 subjects in the treatment (PFT) group and 10 patients in the control group, who had all undergone elective cardiac surgery and were ventilated in the intensive care unit (ICU) afterwards. The PFT was placed on admission to the ICU. In the control group a standard nasogastric tube (NGT) was inserted. Specimens were collected by suctioning from the oropharynx and from above the tracheal tube balloon every hour and from the trachea twice per 8 h shift. Samples were analyzed by ELISA for Pepsin A, as a marker for secretions of gastric origin. Esophageal pressure monitoring (as a measure of pleural pressure), which is an intrinsic ability of the PFT device, was also noted throughout the study – for future integration in mechanical ventilation strategies. Results: The two groups were comparable with regard to demographics and duration of ventilation. There was a larger number of specimens positive for Pepsin A in the control group in the oropharynx (p < 0.0001) and above the ETT cuff (p = 0.0001), but not in the trachea (p = 0.0603), using the Wald Chi-squared test. However, when comparing mean concentrations of Pepsin at the three sites, there was a statistically higher concentration in the control group in the oropharynx, above the ETT and in the trachea, compared to the PFT group. Conclusion: The PFT reduced the amount of GER in ventilated patients. A larger study is required to determine whether this translates to a reduction in VAP. Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12618000669291. Keywords: Ventilator associated incident, Reflux prevention, VA

Wire-guided cannulation versus contrast-guided cannulation in pediatric endoscopic retrograde cholangiopancreatography

Background/Aim: Wire-guided cannulation (WGC) of the common bile duct may be associated with fewer complications and higher success rate compared with contrast-guided cannulation (CGC) in adults. Data in children are lacking. The aim of this study was to compare the successful cannulation and complication rate of WGC and CGC in pediatric endoscopic retrograde cholangiopancreatography (ERCP). Patients and Methods: We report a retrospective cohort study comparing WGC to CGC in a pediatric cohort. We reviewed the medical records of 167 children who underwent ERCP over a 10-year time period (CGC, 1999-2003, WGC, 2003-2009). Indications, findings, and success were analyzed. Results: A total of 93 patients (56%) underwent WGC and 74 (44%) CGC. Children in the WGC group were younger (9.5 ± 4.7 vs. 11.5 ± 4.6 years in CGC; P = 0.006) and underwent more therapeutic ERCP interventions (70% vs. 40% in CGC), whereas diagnostic ERCP was more common in the CGC group (60%; P < 0.005). The overall success (96%) and complication rate (8%) were identical in both groups but a trend toward a reduction in the complication rate over time was noted in the WGC group. Post-ERCP pancreatitis (PEP) was documented in one patient in the WGC group (1.1%) and three patients (4.2%) in the CGC group (P-NS). Conclusion: The success and complication rate in both CGC and WGC are comparable in children but considering the patient and procedure complexity and the trend toward lower PEP in the WGC group, WGC may be the preferable cannulation technique for ERCP in children

A CARD9 polymorphism is associated with decreased likelihood of persistent conjugated hyperbilirubinemia in intestinal failure.

Recently, genetic associations have been described in intestinal transplants. Namely, Crohn's disease susceptibility gene NOD2 polymorphisms have been reported to be more prevalent in patients with graft failure following intestinal transplantation (IT). Therefore, we sought to determine if polymorphisms in the NOD2 signaling cascade, including NOD2, CARD9, RAC1 and ATG16L1 are associated with intestinal failure (IF) or its complications. We carried out a cross-sectional study of 59 children with IF and 500 healthy Caucasian controls. Using the Taqman platform we determined the prevalence of NOD2 as well as ATG16L1, RAC1 and CARD9 SNPs. NOD2 pathway polymorphisms were evaluated in relation to outcomes of episodes of sepsis, ICU admissions, hyperbilirubinemia and need for IT. We found that the minor allele of a CARD9 SNP was associated with protection from developing IF when compared to healthy controls and was also associated with decreased odds of sustained conjugated hyperbilirubinemia. Therefore, IF patients with CARD9 polymorphism are less likely to develop progressive liver disease and suggests that host innate immunity may play a role in IF associated liver disease

Gastric Flora in Gastrostomy Fed Children with Neurological Impairment on Antacid Medication

This prospective cohort study aimed to: (1) describe types, concentrations and sensitivity profiles of bacteria found in gastric aspirates of neurologically impaired children; (2) compare flora between outpatients and those admitted with aspiration pneumonia; and (3) examine predictors of bacterial colonization. Gastric aspirates from gastrostomy fed, neurologically impaired children on antacid medication were measured for pH and sent for microbiological testing. The outpatient arm included 26 children at their baseline; the inpatient arm included 31 children with a clinical diagnosis of aspiration pneumonia. Descriptive statistics summarized the ecology and resistance patterns of microbial flora. Predictors of total bacterial colonization were explored with linear regression. High concentrations of potentially pathogenic fecal-type bacteria were detected in 50/57 (88%) gastric aspirates. pH was found to be the only predictor of bacterial growth; children with gastric pH &ge; 4 had significantly higher concentrations of aerobic growth, while those with no bacterial growth had a pH &lt; 4. Further studies to evaluate optimal gastric pH, the role of gastric bacteria in causing aspiration pneumonia, and the optimal empiric therapy for aspiration pneumonia are recommended

Kidney disease and organ transplantation in methylmalonic acidaemia.

OBJECTIVES: MMA is associated with chronic tubulointerstitial nephritis and a progressive decline in GFR. Optimal management of these children is uncertain. Our objectives were to document the pre-, peri-, and post-transplant course of all children with MMA who underwent liver or combined liver-kidney transplant in our centers. DESIGN AND METHODS: Retrospective chart review of all cases of MMA who underwent organ transplantation over the last 10 years. RESULTS: Five children with MMA underwent liver transplant (4/5) and combined liver-kidney transplant (1/5). Three were Mut CONCLUSIONS: MMA is a complex metabolic disorder. Renal disease can continue to progress post-liver transplant and close follow-up is warranted. More research is needed to clarify best screening GFR method in patients with MMA. Whether liver transplant alone, continued protein restriction, or the addition of antioxidants post-transplant can halt the progression of renal disease remains unclear