RARE DISEASE
Microvillus inclusion disease
Microvillus inclusion disease
Microvillus inclusion disease
Synonyms: Congenital microvillous atrophy, Congenital microvillus atrophy, MVID, Microvillous inclusion disease
Synonyms: Congenital microvillous atrophy, Congenital microvillus atrophy, MVID, Microvillous inclusion disease
Synonyms: Congenital microvillous atrophy, Congenital microvillus atrophy, MVID, Microvillous inclusion disease
Drug discovery
5
drugs
With orphan designations
Overview
Microvillus inclusion disease (MVID) is an autosomal recessive congenital enteropathy characterized by intractable secretory diarrhea starting in early infancy, caused by MYO5B, STX3, or STXBP2 mutations. These mutations disrupt enterocyte apical trafficking, resulting in malabsorption, microvillus atrophy, and cytoplasmic inclusions. Diagnosis relies on duodenal biopsy with electron microscopy. Management requires life-long parenteral nutrition (PN), though complications like PN-associated liver disease and sepsis are common. Intestinal transplantation remains the only curative option but carries significant risks [1][5][16][19].
Burden
Therapies
Parenteral nutrition: Lifelong requirement for 90% of patients, with intestinal transplantation considered for PN failure (5-year survival ~60%) [3][11][19]
Pharmacological: Limited efficacy; antisecretory agents (e.g., Crofelemer) may reduce stool output in select cases [3][7]
Experimental: Gamma-secretase inhibitors (e.g., DAPT) show reversal of microvillus defects in enteroid models [7][14]
Categories: rare gastroenterological diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
82 drug discovery papers about Microvillus inclusion disease, with 2 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
82 drug discovery papers about Microvillus inclusion disease, with 2 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-12 | Enterocyte trafficking proteins and the pathophysiological consequences of their sortopathies
Abstract Objective We synthesised current evidence on enterocyte trafficking proteins and elucidated the molecular mechanisms by which their dysfunction contributes to intestinal disease. Methods Search was conducted in PubMed/MEDLINE, Web of Science, and Wiley Online Library for studies published between January 2000 and March 2026, following PRISMA 2020 guidelines. Studies involving enterocyte trafficking proteins were included based on predefined PICO criteria. Results Thirty-six studies were included, identifying key trafficking regulators, including Rab8a, Rab11a, MYO5B, MYO1A, MYO6, syntaxin 3, MUNC18-2, and SNX27, as essential for enterocyte protein sorting and polarity. Six major mechanisms of dysfunction were observed, involving defects in protein maturation, vesicle formation, Rab-mediated trafficking, SNARE-dependent fusion, motor-driven transport, and endosomal recycling. These disruptions converge into three main pathological processes: impaired apical delivery, defective endocytic retrieval, and failed exocytic fusion, ultimately leading to severe congenital enteropathies such as microvillus inclusion disease, chylomicron retention disease, and STXBP2-associated enteropathy. Conclusion Enterocyte trafficking proteins are fundamental determinants of epithelial polarity and intestinal function. Their dysfunction drives a spectrum of severe intestinal disorders through converging mechanisms of protein mislocalisation and barrier disruption. Advancing diagnostic approaches and developing targeted therapies aimed at restoring intracellular trafficking pathways represent critical priorities for improving patient outcomes.
2026-07-17 | Long-term clinical trajectory of microvillus inclusion disease associated with STXBP2-related familial hemophagocytic lymphohistiocytosis type 5: A case report.
Familial hemophagocytic lymphohistiocytosis type 5 is caused by biallelic pathogenic variants in STXBP2, which encodes syntaxin-binding protein, a key regulator of vesicle trafficking. In addition to immune dysregulation, patients with familial hemophagocytic lymphohistiocytosis type 5 may present with severe, persistent diarrhea associated with microvillus inclusion disease. However, the long-term clinical course of microvillus inclusion disease in this context remains poorly characterized due to limited survival beyond early childhood. We report a 22-year-old male with familial hemophagocytic lymphohistiocytosis type 5 who developed chronic diarrhea in infancy that persisted despite following bone marrow transplantation. The diagnosis of microvillus inclusion disease was established 16 years after transplantation based on characteristic histopathological findings. The patient also developed Fanconi syndrome, a rare complication in this setting, which improved following intensification of parenteral nutrition. Long-term follow-up revealed that the patient was dependent on parenteral nutrition not only for caloric intake but also for the correction of electrolyte imbalance. Growth retardation and multiple endocrine abnormalities improved with nutritional optimization, highlighting the systemic impact of chronic undernutrition. This patient expands the long-term extrahematopoietic phenotype of STXBP2-related familial hemophagocytic lymphohistiocytosis type 5 and underscores the importance of individualized nutritional management.
2026-05-20 | The UNC45A–MYO5B Axis in Enterohepatic Disorders
Defects in epithelial polarity and apical trafficking underlie a spectrum of rare enterohepatic disorders, including microvillus inclusion disease (MVID) and familial intrahepatic cholestasis (FIC/PFIC). This thesis investigates the molecular relationship between the myosin co-chaperone UNC45A and the motor protein MYO5B, two proteins associated with overlapping intestinal and hepatic phenotypes.
Using intestinal epithelial and hepatocellular models, this work demonstrates that UNC45A is required for MYO5B protein stability and proper Rab11A-dependent apical recycling trafficking. Loss of UNC45A disrupts epithelial polarity, impairs microvillus formation, and induces MVID-like cellular defects. Mechanistic studies further show that specific UNC45A variants impair protein stability and chaperone-associated trafficking pathways. In addition, this thesis explores the pathogenesis of MYO5B-associated cholestasis and evaluates the therapeutic potential of ileal bile acid transporter inhibition in UNC45A-associated cholestatic disease.
Together, these findings establish a functional UNC45A–MYO5B axis linking rare enteropathic and cholestatic disorders at the molecular level and provide new insights into the regulation of epithelial polarity and apical membrane trafficking in the enterohepatic system.
2026-03-30 | Microvillus inclusion disease-associated MYO5B deficiency impairs endosome-to-mitochondrion iron transfer.
MYO5B deficiency causes microvillus inclusion disease (MVID), characterized by the inability to absorb dietary nutrients and secretory diarrhea. MVID intestinal tissue shows metabolic abnormalities, but the causality with MYO5B and the underlying mechanism are unknown. The aim of this study was to determine the effects of MYO5B deficiency on mitochondria as key regulators of cellular metabolism and the underlying mechanism. Intestinal tissue from MVID patients and inducible intestine-specific myo5b-knockout (KO) mouse were examined by using light and large-scale scanning transmission electron microscopy. CRISPR-Cas9 was used to generate MYO5B KO intestinal Caco2 cells. Site-directed mutagenesis was performed to generate MYO5B mutants. Fluorescence-based indicators of mitochondrial membrane potential and iron levels, analyses of carbonylated protein residues from isolated mitochondria, and high-resolution respirometry were used to assess mitochondrial homeostasis and function. MYO5B-deficient Caco2 cells showed fragmented and swollen mitochondria, reduced intra-mitochondrial cristae, defective aerobic respiration, reduced mitochondrial membrane potential, and increased mitochondrial oxidative stress. Introduction of a myc-tagged full-length MYO5B in MYO5B KO cells restored membrane potential, whereas the MVID-causing MYO5B-p.(Pro660Leu) variant and the MYO5B-p.(Lys1534Ala) and -p.(Leu1597Pro) mutants did not, demonstrating causality. Quantitative 3D fluorescence microscopy revealed close associations between mitochondria and MYO5B-positive endosomes carrying the iron-transporting transferrin. Associations between transferrin-loaded endosomes and mitochondria were diminished in MYO5B-depleted Caco2 cells. MYO5B-deficient Caco2 cells showed reduced mitochondrial iron content and an accumulation of iron in the endosomal system. MYO5B deficiency impairs endosome-to-mitochondrial iron transfer, leading to mitochondrial dysfunction. These results offer a novel therapeutic avenue aimed at restoring mitochondrial function in MVID.
2026-02-12 | Myosin 5b deficiency alters liver proliferation, zonation, and bile acid composition.
Myosin 5b (Myo5b) is a motor protein critical for trafficking proteins to the apical surface of intestinal epithelial cells. Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), a congenital diarrhea disorder that often leads to liver cholestasis. While Myo5b's role in the intestine is well characterized, its function in the liver remains unclear. To define the hepatic consequences of Myo5b loss, we analyzed germline Myo5b knockout (KO) mice. Bulk RNAseq of KO livers revealed significant transcriptomic alterations, notably downregulation of genes linked to cell proliferation. Immunostaining confirmed reduced Ki67, phospho-histone H3, and cyclin D1 expression, along with impaired growth of liver organoids in Myo5b-deficient mice. Histology and lipid staining showed steatosis and enlarged lipid droplets, with gene signatures favoring lipogenesis and ketogenesis in mice lacking Myo5b. Myo5b KO livers also displayed disrupted zonated gene expression and loss of zone 1 and zone 3 markers. Bile acid profiling revealed reduced hepatic bile acid levels, decreased expression of classical pathway genes (Cyp7a1, Cyp7b1), and compensatory upregulation of Cyp27a1. In the ileum, we observed mislocalization of the apical bile acid transporter ASBT and decreased levels of basolateral OSTβ, leading to impaired enterohepatic recycling and increased luminal bile acids. These findings reveal a previously unrecognized role for Myo5b in liver proliferation, metabolic zonation, and bile acid homeostasis, highlighting its importance in maintaining hepatobiliary function.
2026-08-12 | Enterocyte trafficking proteins and the pathophysiological consequences of their sortopathies
Abstract Objective We synthesised current evidence on enterocyte trafficking proteins and elucidated the molecular mechanisms by which their dysfunction contributes to intestinal disease. Methods Search was conducted in PubMed/MEDLINE, Web of Science, and Wiley Online Library for studies published between January 2000 and March 2026, following PRISMA 2020 guidelines. Studies involving enterocyte trafficking proteins were included based on predefined PICO criteria. Results Thirty-six studies were included, identifying key trafficking regulators, including Rab8a, Rab11a, MYO5B, MYO1A, MYO6, syntaxin 3, MUNC18-2, and SNX27, as essential for enterocyte protein sorting and polarity. Six major mechanisms of dysfunction were observed, involving defects in protein maturation, vesicle formation, Rab-mediated trafficking, SNARE-dependent fusion, motor-driven transport, and endosomal recycling. These disruptions converge into three main pathological processes: impaired apical delivery, defective endocytic retrieval, and failed exocytic fusion, ultimately leading to severe congenital enteropathies such as microvillus inclusion disease, chylomicron retention disease, and STXBP2-associated enteropathy. Conclusion Enterocyte trafficking proteins are fundamental determinants of epithelial polarity and intestinal function. Their dysfunction drives a spectrum of severe intestinal disorders through converging mechanisms of protein mislocalisation and barrier disruption. Advancing diagnostic approaches and developing targeted therapies aimed at restoring intracellular trafficking pathways represent critical priorities for improving patient outcomes.
2026-07-17 | Long-term clinical trajectory of microvillus inclusion disease associated with STXBP2-related familial hemophagocytic lymphohistiocytosis type 5: A case report.
Familial hemophagocytic lymphohistiocytosis type 5 is caused by biallelic pathogenic variants in STXBP2, which encodes syntaxin-binding protein, a key regulator of vesicle trafficking. In addition to immune dysregulation, patients with familial hemophagocytic lymphohistiocytosis type 5 may present with severe, persistent diarrhea associated with microvillus inclusion disease. However, the long-term clinical course of microvillus inclusion disease in this context remains poorly characterized due to limited survival beyond early childhood. We report a 22-year-old male with familial hemophagocytic lymphohistiocytosis type 5 who developed chronic diarrhea in infancy that persisted despite following bone marrow transplantation. The diagnosis of microvillus inclusion disease was established 16 years after transplantation based on characteristic histopathological findings. The patient also developed Fanconi syndrome, a rare complication in this setting, which improved following intensification of parenteral nutrition. Long-term follow-up revealed that the patient was dependent on parenteral nutrition not only for caloric intake but also for the correction of electrolyte imbalance. Growth retardation and multiple endocrine abnormalities improved with nutritional optimization, highlighting the systemic impact of chronic undernutrition. This patient expands the long-term extrahematopoietic phenotype of STXBP2-related familial hemophagocytic lymphohistiocytosis type 5 and underscores the importance of individualized nutritional management.
2026-05-20 | The UNC45A–MYO5B Axis in Enterohepatic Disorders
Defects in epithelial polarity and apical trafficking underlie a spectrum of rare enterohepatic disorders, including microvillus inclusion disease (MVID) and familial intrahepatic cholestasis (FIC/PFIC). This thesis investigates the molecular relationship between the myosin co-chaperone UNC45A and the motor protein MYO5B, two proteins associated with overlapping intestinal and hepatic phenotypes.
Using intestinal epithelial and hepatocellular models, this work demonstrates that UNC45A is required for MYO5B protein stability and proper Rab11A-dependent apical recycling trafficking. Loss of UNC45A disrupts epithelial polarity, impairs microvillus formation, and induces MVID-like cellular defects. Mechanistic studies further show that specific UNC45A variants impair protein stability and chaperone-associated trafficking pathways. In addition, this thesis explores the pathogenesis of MYO5B-associated cholestasis and evaluates the therapeutic potential of ileal bile acid transporter inhibition in UNC45A-associated cholestatic disease.
Together, these findings establish a functional UNC45A–MYO5B axis linking rare enteropathic and cholestatic disorders at the molecular level and provide new insights into the regulation of epithelial polarity and apical membrane trafficking in the enterohepatic system.
2026-03-30 | Microvillus inclusion disease-associated MYO5B deficiency impairs endosome-to-mitochondrion iron transfer.
MYO5B deficiency causes microvillus inclusion disease (MVID), characterized by the inability to absorb dietary nutrients and secretory diarrhea. MVID intestinal tissue shows metabolic abnormalities, but the causality with MYO5B and the underlying mechanism are unknown. The aim of this study was to determine the effects of MYO5B deficiency on mitochondria as key regulators of cellular metabolism and the underlying mechanism. Intestinal tissue from MVID patients and inducible intestine-specific myo5b-knockout (KO) mouse were examined by using light and large-scale scanning transmission electron microscopy. CRISPR-Cas9 was used to generate MYO5B KO intestinal Caco2 cells. Site-directed mutagenesis was performed to generate MYO5B mutants. Fluorescence-based indicators of mitochondrial membrane potential and iron levels, analyses of carbonylated protein residues from isolated mitochondria, and high-resolution respirometry were used to assess mitochondrial homeostasis and function. MYO5B-deficient Caco2 cells showed fragmented and swollen mitochondria, reduced intra-mitochondrial cristae, defective aerobic respiration, reduced mitochondrial membrane potential, and increased mitochondrial oxidative stress. Introduction of a myc-tagged full-length MYO5B in MYO5B KO cells restored membrane potential, whereas the MVID-causing MYO5B-p.(Pro660Leu) variant and the MYO5B-p.(Lys1534Ala) and -p.(Leu1597Pro) mutants did not, demonstrating causality. Quantitative 3D fluorescence microscopy revealed close associations between mitochondria and MYO5B-positive endosomes carrying the iron-transporting transferrin. Associations between transferrin-loaded endosomes and mitochondria were diminished in MYO5B-depleted Caco2 cells. MYO5B-deficient Caco2 cells showed reduced mitochondrial iron content and an accumulation of iron in the endosomal system. MYO5B deficiency impairs endosome-to-mitochondrial iron transfer, leading to mitochondrial dysfunction. These results offer a novel therapeutic avenue aimed at restoring mitochondrial function in MVID.
2026-02-12 | Myosin 5b deficiency alters liver proliferation, zonation, and bile acid composition.
Myosin 5b (Myo5b) is a motor protein critical for trafficking proteins to the apical surface of intestinal epithelial cells. Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), a congenital diarrhea disorder that often leads to liver cholestasis. While Myo5b's role in the intestine is well characterized, its function in the liver remains unclear. To define the hepatic consequences of Myo5b loss, we analyzed germline Myo5b knockout (KO) mice. Bulk RNAseq of KO livers revealed significant transcriptomic alterations, notably downregulation of genes linked to cell proliferation. Immunostaining confirmed reduced Ki67, phospho-histone H3, and cyclin D1 expression, along with impaired growth of liver organoids in Myo5b-deficient mice. Histology and lipid staining showed steatosis and enlarged lipid droplets, with gene signatures favoring lipogenesis and ketogenesis in mice lacking Myo5b. Myo5b KO livers also displayed disrupted zonated gene expression and loss of zone 1 and zone 3 markers. Bile acid profiling revealed reduced hepatic bile acid levels, decreased expression of classical pathway genes (Cyp7a1, Cyp7b1), and compensatory upregulation of Cyp27a1. In the ileum, we observed mislocalization of the apical bile acid transporter ASBT and decreased levels of basolateral OSTβ, leading to impaired enterohepatic recycling and increased luminal bile acids. These findings reveal a previously unrecognized role for Myo5b in liver proliferation, metabolic zonation, and bile acid homeostasis, highlighting its importance in maintaining hepatobiliary function.
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Drug Discovery Landscape
5 orphan drug designations for Microvillus inclusion disease.
5 orphan drug designations for Microvillus inclusion disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
crofelemer | small molecules | FDA | 2023-02-27 | — | Napo Pharmaceuticals Inc. |
Crofelemer | small molecules | EMA | 2022-10-11 | — | Napo Therapeutics S.p.A. |
Retinyl Palmitate, Alisitol (herbal extract), Zn Gluconate | small molecules | FDA | 2021-03-18 | — | Dmitry V. Kravtsov, M.D. |
Alisitol, retinol palmitate, zinc gluconate | small molecules | EMA | 2020-11-13 | — | Vanessa Research Spain S.L. |
racecadotril | small molecules | FDA | 2020-04-13 | — | RNR BioMedical Inc. |
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