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

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

Oral vancomycin and gentamicin for treatment of very early onset inflammatory bowel disease

Background: The pathogenesis of inflammatory bowel disease (IBD) is complex and involves the contribution of genetic and environmental factors. Many patients with very early onset IBD are difficult to treat. The current antibiotic medication that targets gram-negative and anaerobic bacteria provides only moderate efficacy in subsets of patients with IBD. Methods: We report a case series of 5 children with a mean age of 1.6 years (range 6 months to 2.7 years) during IBD onset, who were previously refractory to standard treatments and who received oral vancomycin with or without gentamicin. Results: Four out of 5 children demonstrated substantial therapeutic effect, and the effect was sustained in 3 children over a follow-up period of 12-33 months. Conclusion: Our findings are consistent with model systems and suggest that randomized trials are required to establish whether a change in therapeutic paradigm, that is, targeting gram-positive bacteria with nonabsorbable antibiotics, may have therapeutic benefits

Oral vancomycin and gentamicin for treatment of very early onset inflammatory bowel disease

Background: The pathogenesis of inflammatory bowel disease (IBD) is complex and involves the contribution of genetic and environmental factors. Many patients with very early onset IBD are difficult to treat. The current antibiotic medication that targets gram-negative and anaerobic bacteria provides only moderate efficacy in subsets of patients with IBD. Methods: We report a case series of 5 children with a mean age of 1.6 years (range 6 months to 2.7 years) during IBD onset, who were previously refractory to standard treatments and who received oral vancomycin with or without gentamicin. Results: Four out of 5 children demonstrated substantial therapeutic effect, and the effect was sustained in 3 children over a follow-up period of 12-33 months. Conclusion: Our findings are consistent with model systems and suggest that randomized trials are required to establish whether a change in therapeutic paradigm, that is, targeting gram-positive bacteria with nonabsorbable antibiotics, may have therapeutic benefits

Supplementary Material for: Oral Vancomycin and Gentamicin for Treatment of Very Early Onset Inflammatory Bowel Disease

<p><b><i>Background:</i></b> The pathogenesis of inflammatory bowel disease (IBD) is complex and involves the contribution of genetic and environmental factors. Many patients with very early onset IBD are difficult to treat. The current antibiotic medication that targets gram-negative and anaerobic bacteria provides only moderate efficacy in subsets of patients with IBD. <b><i>Methods:</i></b> We report a case series of 5 children with a mean age of 1.6 years (range 6 months to 2.7 years) during IBD onset, who were previously refractory to standard treatments and who received oral vancomycin with or without gentamicin. <b><i>Results:</i></b> Four out of 5 children demonstrated substantial therapeutic effect, and the effect was sustained in 3 children over a follow-up period of 12-33 months. <b><i>Conclusion:</i></b> Our findings are consistent with model systems and suggest that randomized trials are required to establish whether a change in therapeutic paradigm, that is, targeting gram-positive bacteria with nonabsorbable antibiotics, may have therapeutic benefits.</p

Nutritional Lipids and Mucosal Inflammation

Inflammatory bowel disease (IBD) is characterized by chronic relapsing inflammation in the intestine. Given their role in regulation of inflammation, long-chain n-3 polyunsaturated fatty acids (PUFAs) represent a potential supplementary therapeutic approach to current drug regimens used for IBD. Mechanistically, there is ample evidence for an anti-inflammatory and pro-resolution effect of long-chain n-3 PUFAs after they incorporate into cell membrane phospholipids. They disrupt membrane rafts and when released from the membrane suppress inflammatory signaling by activating PPAR-γ and free fatty acid receptor 4; furthermore, they shift the lipid mediator profile from pro-inflammatory eicosanoids to specialized pro-resolving mediators. The allocation of long-chain n-3 PUFAs also leads to a higher microbiome diversity in the gut, increases short-chain fatty acid-producing bacteria, and improves intestinal barrier function by sealing epithelial tight junctions. In line with these mechanistic studies, most epidemiological studies support a beneficial effect of long-chain n-3 PUFAs intake on reducing the incidence of IBD. However, the results from intervention trials on the prevention of relapse in IBD patients show no or only a marginal effect of long-chain n-3 PUFAs supplementation. In light of the current literature, international recommendations are supported that adequate diet-derived n-3 PUFAs might be beneficial in maintaining remission in IBD patients. © 2020 Wiley-VCH GmbHISSN:1613-4125ISSN:1613-413

Infliximab in young paediatric IBD patients: it is all about the dosing

Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients < 10 years. TDM data were collected retrospectively in 14 centres. Children treated with IFX were included if IFX was started as IBD treatment at age < 10 years (young patients, YP) and PK data were available. Older IBD patients aged 10–18 years were used as controls (older patients, OP). Two hundred and fifteen paediatric inflammatory bowel disease (PIBD) patients were eligible for the study (110 < 10 year; 105 ≥ 10 years). Median age was 8.3 years (IQR 6.9–8.9) in YP compared with 14.3 years (IQR 12.8–15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 μg/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0–12.9) vs. OP; 5.5 mg/kg (IQR 5.0–9.3); p < 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI − 1.2 to − 1.01); p < 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP; p = 0.56). Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years.What is Known?What is New