Abstract
ABSTRACTCongenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDDENT) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDDENT. Here, we review recent progress in understanding the cellular mechanisms of CDDENT. We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDDENT and expediting the discovery of novel therapeutic strategies.
Highlights
Congenital diarrheal disorders (CDDs) are a group of rare inherited intestinal disorders that are characterized by persistent life-threatening intractable diarrhea and nutrient malabsorption, which emerge during the first weeks of life
CDDs associated with enterocyte defects include disorders that can be treated with nutrition therapy
Other CDDENT require life-long total parenteral nutrition (TPN; see Box 1 for a glossary of clinical terms used in this article) to receive adequate nutrition, and are a leading indication for
Summary
Congenital diarrheal disorders (CDDs) are a group of rare inherited intestinal disorders that are characterized by persistent life-threatening intractable diarrhea and nutrient malabsorption, which emerge during the first weeks of life. Depending on the type of mutation, these proteins are either not expressed, not correctly transported to the brush border membrane, or display defects in their activity, resulting in defective digestion, absorption and/or transport of nutrients, metabolites and/or electrolytes at the enterocyte brush border. CDDENT associated with functional defects of brush-border-associated enzymes and transporter proteins are typically not associated with abnormal enterocyte organization, as examined by histology. The plasma membrane domains are equipped with distinct enzymes and transporter proteins that control the metabolism, absorption and/ or secretion of nutrients, metabolites and electrolytes between the gut lumen, cell interior and body tissue. Diverse molecular mechanisms of CDDENT underlying clinical presentation and diagnosis Based on recent molecular and cell biological studies, enterocyte defects that underlie CDDENT can be divided into defects of (i) brush-border-associated enzymes and transporter proteins; (ii) intracellular protein transport; (iii) intracellular lipid transport and metabolism; and (iv) intestinal barrier function (Table 1).
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