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Microvillus Inclusion Disease and Related Congenital Diarrheal Diseases
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Microvillus Inclusion Disease and Related Congenital Diarrheal Diseases

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 20573

Special Issue Editors

Prof. Dr. Sven van IJzendoorn

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Guest Editor
Department of Biomedical Sciences of Cells and Systems, Section Molecular Cell Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Interests: epithelial polarity; intracellular trafficking; rare diseases; microvillus inclusion disease
Prof. Dr. Edmond H. H. M. Rings

E-Mail Website
Guest Editor
Departments of Pediatrics, Leiden University Medical Center, Willem-Alexander Children’s Hospital, Leiden and Erasmus Medical Center, Sophia Children’s hospital, Rotterdam, The Netherlands
Interests: intestinal failure; intestinal rehabilitation; congenital diarrheal diseases; microvillus inclusion disease

Special Issue Information

Dear Colleagues,

Microvillus inclusion disease (MVID) is one of the most severe congenital diarrheal diseases. Patients suffer from intractable secretory diarrhea, nutrient malabsorption, and failure to thrive, and depend on life-long total parenteral nutrition for their survival. Since the discovery of causative gene mutations, a great deal of progress has been made with regard to the etiology, diagnosis, and the underlying genetics and mechanisms of MVID. In addition, we have learned that MVID is an evolving condition that often presents with extra-intestinal symptoms, including but not restricted to cholestatic liver disease. We have also learned that MVID may appear as part of other congenital diseases such as familial hemophagocytic lymphohistiocytosis type 5. Furthermore, an open-access online MVID patient registry has been initiated (www.mvid-central.org). Despite these exciting new developments, prognosis remains poor, and a cure or effective treatment is urgently needed. With this Special Issue, we hope to encourage submissions that embark on genetic diagnosis and counselling, pharmacological interventions, follow-up of patients after conservative and/or surgical treatment (including liver/intestinal transplantation), and on new insights of mechanisms of disease related to the intestinal and extra-intestinal manifestations of microvillus inclusion disease and related congenital diarrheal diseases in childhood. 

Prof. Dr. Sven van IJzendoorn
Prof. Dr. Edmond H. H. M. Rings
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • microvillus inclusion disease
  • intractable diarrhea of infancy
  • intestinal failure
  • congenital diarrheal disease
  • microvillus atrophy
  • MYO5B
  • STX3

Published Papers (7 papers)

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Research

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11 pages, 1067 KiB  
Article
Fetal Bowel Abnormalities Suspected by Ultrasonography in Microvillus Inclusion Disease: Prevalence and Clinical Significance
by Yue Sun, Changsen Leng and Sven C. D. van Ijzendoorn
J. Clin. Med. 2022, 11(15), 4331; https://doi.org/10.3390/jcm11154331 - 26 Jul 2022
Cited by 1 | Viewed by 1477
Abstract
Microvillus inclusion disease (MVID) is a rare, inherited, congenital, diarrheal disorder that is invariably fatal if left untreated. Within days after birth, MVID presents as a life-threatening emergency characterized by severe dehydration, metabolic acidosis, and weight loss. Diagnosis is cumbersome and can take [...] Read more.
Microvillus inclusion disease (MVID) is a rare, inherited, congenital, diarrheal disorder that is invariably fatal if left untreated. Within days after birth, MVID presents as a life-threatening emergency characterized by severe dehydration, metabolic acidosis, and weight loss. Diagnosis is cumbersome and can take a long time. Whether MVID could be diagnosed before birth is not known. Anecdotal reports of MVID-associated fetal bowel abnormalities suspected by ultrasonography (that is, dilated bowel loops and polyhydramnios) have been published. These are believed to be rare, but their prevalence in MVID has not been investigated. Here, we have performed a comprehensive retrospective study of 117 published MVID cases spanning three decades. We find that fetal bowel abnormalities in MVID occurred in up to 60% of cases of MVID for which prenatal ultrasonography or pregnancy details were reported. Suspected fetal bowel abnormalities appeared in the third trimester of pregnancy and correlated with postnatal, early-onset diarrhea and case-fatality risk during infancy. Fetal bowel dilation correlated with MYO5B loss-of-function variants. In conclusion, MVID has already started during fetal life in a significant number of cases. Genetic testing for MVID-causing gene variants in cases where fetal bowel abnormalities are suspected by ultrasonography may allow for the prenatal diagnosis of MVID in a significant percentage of cases, enabling optimal preparation for neonatal intensive care. Full article
(This article belongs to the Special Issue Microvillus Inclusion Disease and Related Congenital Diarrheal Diseases)
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22 pages, 14600 KiB  
Article
Loss of Serum Glucocorticoid-Inducible Kinase 1 SGK1 Worsens Malabsorption and Diarrhea in Microvillus Inclusion Disease (MVID)
by Md Kaimul Ahsan, Diego Carlos dos Reis, Andrea Barbieri, Kaelyn D. Sumigray, Timothy Nottoli, Pedro J. Salas and Nadia A. Ameen
J. Clin. Med. 2022, 11(14), 4179; https://doi.org/10.3390/jcm11144179 - 19 Jul 2022
Cited by 3 | Viewed by 1806
Abstract
Microvillus inclusion disease (MVID), a lethal congenital diarrheal disease, results from loss of function mutations in the apical actin motor myosin VB (MYO5B). How loss of MYO5B leads to both malabsorption and fluid secretion is not well understood. Serum glucocorticoid-inducible kinase 1 (SGK1) [...] Read more.
Microvillus inclusion disease (MVID), a lethal congenital diarrheal disease, results from loss of function mutations in the apical actin motor myosin VB (MYO5B). How loss of MYO5B leads to both malabsorption and fluid secretion is not well understood. Serum glucocorticoid-inducible kinase 1 (SGK1) regulates intestinal carbohydrate and ion transporters including cystic fibrosis transmembrane conductance regulator (CFTR). We hypothesized that loss of SGK1 could reduce CFTR fluid secretion and MVID diarrhea. Using CRISPR-Cas9 approaches, we generated R26CreER;MYO5Bf/f conditional single knockout (cMYO5BKO) and R26CreER;MYO5Bf/f;SGK1f/f double knockout (cSGK1/MYO5B-DKO) mice. Tamoxifen-treated cMYO5BKO mice resulted in characteristic features of human MVID including severe diarrhea, microvillus inclusions (MIs) in enterocytes, defective apical traffic, and depolarization of transporters. However, apical CFTR distribution was preserved in crypts and depolarized in villus enterocytes, and CFTR high expresser (CHE) cells were observed. cMYO5BKO mice displayed increased phosphorylation of SGK1, PDK1, and the PDK1 target PKCι in the intestine. Surprisingly, tamoxifen-treated cSGK1/MYO5B-DKO mice displayed more severe diarrhea than cMYO5BKO, with preservation of apical CFTR and CHE cells, greater fecal glucose and reduced SGLT1 and GLUT2 in the intestine. We conclude that loss of SGK1 worsens carbohydrate malabsorption and diarrhea in MVID. Full article
(This article belongs to the Special Issue Microvillus Inclusion Disease and Related Congenital Diarrheal Diseases)
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9 pages, 1129 KiB  
Article
Risk and Clinical Significance of Idiopathic Preterm Birth in Microvillus Inclusion Disease
by Changsen Leng, Yue Sun and Sven C. D. van IJzendoorn
J. Clin. Med. 2021, 10(17), 3935; https://doi.org/10.3390/jcm10173935 - 31 Aug 2021
Cited by 1 | Viewed by 1680
Abstract
Microvillus inclusion disease (MVID) is a rare enteropathy caused by mutations in the MYO5B or STX3 gene. MVID is a disease that is difficult to manage with clinical heterogeneity. Therefore, knowledge about factors influencing MVID morbidity and mortality is urgently needed. Triggered by [...] Read more.
Microvillus inclusion disease (MVID) is a rare enteropathy caused by mutations in the MYO5B or STX3 gene. MVID is a disease that is difficult to manage with clinical heterogeneity. Therefore, knowledge about factors influencing MVID morbidity and mortality is urgently needed. Triggered by a recent study that reported a high percentage of preterm births in twelve cases of MVID, we have conducted a comprehensive retrospective study involving 88 cases of MVID with reported gestational ages. We found that moderate to late preterm birth occurred in more than half of all cases, and this was particularly prominent in MYO5B-associated MVID. Preterm birth in MVID counterintuitively correlated with higher birth weight percentiles, and correlated with higher stool outputs and a significantly shorter average survival time. Data from this study thus demonstrate an increased risk of preterm birth in MYO5B-associated MVID, with a clinical impact on morbidity and mortality. Adverse effects associated with preterm birth should be taken into account in the care of children diagnosed with MVID. Documentation of gestational age may contribute to a better prognostic risk assessment in MVID. Full article
(This article belongs to the Special Issue Microvillus Inclusion Disease and Related Congenital Diarrheal Diseases)
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29 pages, 8792 KiB  
Article
Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations
by Michael W. Hess, Iris M. Krainer, Przemyslaw A. Filipek, Barbara Witting, Karin Gutleben, Ilja Vietor, Heinz Zoller, Denise Aldrian, Ekkehard Sturm, James R. Goldenring, Andreas R. Janecke, Thomas Müller, Lukas A. Huber and Georg F. Vogel
J. Clin. Med. 2021, 10(9), 1901; https://doi.org/10.3390/jcm10091901 - 28 Apr 2021
Cited by 6 | Viewed by 3207
Abstract
Mutations in the actin motor protein myosinVb (myo5b) cause aberrant apical cargo transport and the congenital enteropathy microvillus inclusion disease (MVID). Recently, missense mutations in myo5b were also associated with progressive familial intrahepatic cholestasis (MYO5B-PFIC). Here, we thoroughly characterized the ultrastructural and immuno-cytochemical [...] Read more.
Mutations in the actin motor protein myosinVb (myo5b) cause aberrant apical cargo transport and the congenital enteropathy microvillus inclusion disease (MVID). Recently, missense mutations in myo5b were also associated with progressive familial intrahepatic cholestasis (MYO5B-PFIC). Here, we thoroughly characterized the ultrastructural and immuno-cytochemical phenotype of hepatocytes and duodenal enterocytes from a unique case of an adult MYO5B-PFIC patient who showed constant hepatopathy but only periodic enteric symptoms. Selected data from two other patients supported the findings. Advanced methods such as cryo-fixation, freeze-substitution, immuno-gold labeling, electron tomography and immuno-fluorescence microscopy complemented the standard procedures. Liver biopsies showed mislocalization of Rab11 and bile canalicular membrane proteins. Rab11-positive vesicles clustered around bile canaliculi and resembled subapical clusters of aberrant recycling endosomes in enterocytes from MVID patients. The adult patient studied in detail showed a severe, MVID-specific enterocyte phenotype, despite only a mild clinical intestinal presentation. This included mislocalization of numerous proteins essential for apical cargo transport and morphological alterations. We characterized the heterogeneous population of large catabolic organelles regarding their complex ultrastructure and differential distribution of autophagic and lysosomal marker proteins. Finally, we generated duodenal organoids/enteroids from biopsies that recapitulated all MVID hallmarks, demonstrating the potential of this disease model for personalized medicine. Full article
(This article belongs to the Special Issue Microvillus Inclusion Disease and Related Congenital Diarrheal Diseases)
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15 pages, 1002 KiB  
Article
Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations
by Denise Aldrian, Georg F. Vogel, Teresa K. Frey, Hasret Ayyıldız Civan, Aysel Ünlüsoy Aksu, Yaron Avitzur, Esther Ramos Boluda, Murat Çakır, Arzu Meltem Demir, Caroline Deppisch, Hans-Christoph Duba, Gesche Düker, Patrick Gerner, Jozef Hertecant, Jarmila Hornová, Simone Kathemann, Jutta Koeglmeier, Arsinoi Koutroumpa, Roland Lanzersdorfer, Raffi Lev-Tzion, Rosa Lima, Sahar Mansour, Manfred Meissl, Jan Melek, Mohamad Miqdady, Jorge Hernan Montoya, Carsten Posovszky, Yelena Rachman, Tania Siahanidou, Merit Tabbers, Holm H. Uhlig, Sevim Ünal, Stefan Wirth, Frank M. Ruemmele, Michael W. Hess, Lukas A. Huber, Thomas Müller, Ekkehard Sturm and Andreas R. Janeckeadd Show full author list remove Hide full author list
J. Clin. Med. 2021, 10(3), 481; https://doi.org/10.3390/jcm10030481 - 28 Jan 2021
Cited by 21 | Viewed by 4414
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Microvillus Inclusion Disease and Related Congenital Diarrheal Diseases)
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Review

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17 pages, 689 KiB  
Review
Pharmacological and Parenteral Nutrition-Based Interventions in Microvillus Inclusion Disease
by Changsen Leng, Edmond H. H. M. Rings, Saskia N. de Wildt and Sven C. D. van IJzendoorn
J. Clin. Med. 2021, 10(1), 22; https://doi.org/10.3390/jcm10010022 - 23 Dec 2020
Cited by 6 | Viewed by 2868
Abstract
Microvillus inclusion disease (MVID) is a rare inherited and invariably fatal enteropathy, characterized by severe intractable secretory diarrhea and nutrient malabsorption. No cure exists, and patients typically die during infancy because of treatment-related complications. The need for alternative treatment strategies is evident. Several [...] Read more.
Microvillus inclusion disease (MVID) is a rare inherited and invariably fatal enteropathy, characterized by severe intractable secretory diarrhea and nutrient malabsorption. No cure exists, and patients typically die during infancy because of treatment-related complications. The need for alternative treatment strategies is evident. Several pharmacological interventions with variable successes have been tried and reported for individual patients as part of their clinical care. Unfortunately, these interventions and their outcomes have remained hidden in case reports and have not been reviewed. Further, recent advances regarding MVID pathogenesis have shed new light on the outcomes of these pharmacological interventions and offer suggestions for future clinical research and trials. Hence, an inventory of reported pharmacological interventions in MVID, their rationales and outcomes, and a discussion of these in the light of current knowledge is opportune. Together with a discussion on MVID-specific pharmacokinetic, -dynamic, and -genetic concerns that pose unique challenges regarding pharmacological strategies, we envision that this paper will aid researchers and clinicians in their efforts to develop pharmacological interventions to combat this devastating disease. Full article
(This article belongs to the Special Issue Microvillus Inclusion Disease and Related Congenital Diarrheal Diseases)
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12 pages, 226 KiB  
Review
Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms
by Barun Das and Mamata Sivagnanam
J. Clin. Med. 2021, 10(1), 19; https://doi.org/10.3390/jcm10010019 - 23 Dec 2020
Cited by 15 | Viewed by 4007
Abstract
Congenital tufting enteropathy (CTE) is an autosomal recessive disease of infancy that causes severe intestinal failure with electrolyte imbalances and impaired growth. CTE is typically diagnosed by its characteristic histological features, including villous atrophy, crypt hyperplasia and focal epithelial tufts consisting of densely [...] Read more.
Congenital tufting enteropathy (CTE) is an autosomal recessive disease of infancy that causes severe intestinal failure with electrolyte imbalances and impaired growth. CTE is typically diagnosed by its characteristic histological features, including villous atrophy, crypt hyperplasia and focal epithelial tufts consisting of densely packed enterocytes. Mutations in the EPCAM and SPINT2 genes have been identified as the etiology for this disease. The significant morbidity and mortality and lack of direct treatments for CTE patients demand a better understanding of disease pathophysiology. Here, the latest knowledge of CTE biology is systematically reviewed, including clinical aspects, disease genetics, and research model systems. Particular focus is paid to the pathogenesis of CTE and predicted mechanisms of the disease as these would provide insight for future therapeutic options. The contribution of intestinal homeostasis, including the role of intestinal cell differentiation, defective enterocytes, disrupted barrier and cell–cell junction, and cell-matrix adhesion, is vividly described here (see Graphical Abstract). Moreover, based on the known dynamics of EpCAM signaling, potential mechanistic pathways are highlighted that may contribute to the pathogenesis of CTE due to either loss of EpCAM function or EpCAM mutation. Although not fully elucidated, these pathways provide an improved understanding of this devastating disease. Full article
(This article belongs to the Special Issue Microvillus Inclusion Disease and Related Congenital Diarrheal Diseases)
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