Your browser doesn't support javascript.
loading
: 20 | 50 | 100
1 - 20 de 361
1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(3): 339-344, 2024 Mar 10.
Article Zh | MEDLINE | ID: mdl-38448026

OBJECTIVE: To explore the clinical and genetic characteristics of a neonate with Microvillus inclusion disease (MVID). METHODS: A neonate with MVID admitted to the First Affiliated Hospital of Zhengzhou University in May 2019 was selected as the study subject. Clinical data were collected. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing and multiple ligation-dependent probe amplification (MLPA). A literature was also carried out to summarize the clinical and genetic characteristics of MVID. RESULTS: The prematurely born neonate had presented with unexplained refractory diarrhea and metabolic acidosis. Active symptomatic treatment was ineffective, and the child had died at 2 months old. WES revealed that he had harbored compound heterozygous variants of the MYO5B gene, namely c.1591C>T (p.R531W) and deletion of exon 9. Sanger sequencing showed that the R531W variant was inherited form his father, and MLPA confirmed that the exon 9 deletion was inherited from his mother. Seven children with MVID were reported in China, of which one was lost during follow-up and six had deceased. One hundred eighty eight patients were reported worldwide and only one was cured. The clinical features of MVID had included refractory diarrhea, metabolic acidosis and poor prognosis. CONCLUSION: The child was diagnosed with MVID due to the compound heterozygous variants of the MYO5B gene, which has provided a basis for genetic counseling and prenatal diagnosis.


Acidosis , Malabsorption Syndromes , Microvilli , Mucolipidoses , Myosin Type V , Female , Humans , Infant , Infant, Newborn , Male , Pregnancy , Diarrhea/genetics , Malabsorption Syndromes/genetics , Microvilli/pathology , Mucolipidoses/genetics , Myosin Heavy Chains , Myosin Type V/genetics
2.
Cell Mol Gastroenterol Hepatol ; 17(6): 983-1005, 2024.
Article En | MEDLINE | ID: mdl-38307491

Microvillus inclusion disease (MVID) is a rare condition that is present from birth and affects the digestive system. People with MVID experience severe diarrhea that is difficult to control, cannot absorb dietary nutrients, and struggle to grow and thrive. In addition, diverse clinical manifestations, some of which are life-threatening, have been reported in cases of MVID. MVID can be caused by variants in the MYO5B, STX3, STXBP2, or UNC45A gene. These genes produce proteins that have been functionally linked to each other in intestinal epithelial cells. MVID associated with STXBP2 variants presents in a subset of patients diagnosed with familial hemophagocytic lymphohistiocytosis type 5. MVID associated with UNC45A variants presents in most patients diagnosed with osteo-oto-hepato-enteric syndrome. Furthermore, variants in MYO5B or STX3 can also cause other diseases that are characterized by phenotypes that can co-occur in subsets of patients diagnosed with MVID. Recent studies involving clinical data and experiments with cells and animals revealed connections between specific phenotypes occurring outside of the digestive system and the type of gene variants that cause MVID. Here, we have reviewed these patterns and correlations, which are expected to be valuable for healthcare professionals in managing the disease and providing personalized care for patients and their families.


Malabsorption Syndromes , Microvilli , Mucolipidoses , Phenotype , Humans , Mucolipidoses/genetics , Mucolipidoses/pathology , Microvilli/pathology , Microvilli/genetics , Malabsorption Syndromes/genetics , Malabsorption Syndromes/pathology , Animals , Myosin Type V/genetics , Myosin Type V/metabolism , Mutation , Genetic Predisposition to Disease
3.
Indian J Pediatr ; 91(6): 598-605, 2024 Jun.
Article En | MEDLINE | ID: mdl-38105403

Congenital diarrhea and enteropathies (CODEs) constitute a group of rare genetic disorders characterized by severe diarrhea and malabsorption in the neonatal period or early infancy. Timely diagnosis and treatment is essential to prevent life-threatening complications, including dehydration, electrolyte imbalance, and malnutrition. This review offers a simplified approach to the diagnosis of CODEs, with a specific focus on microvillus inclusion disease (MVID), congenital tufting enteropathy (CTE), congenital chloride diarrhea (CLD), and congenital sodium diarrhea (CSD). Patients with CODEs typically present with severe watery or occasionally bloody diarrhea, steatorrhea, dehydration, poor growth, and developmental delay. Therefore, it is crucial to thoroughly evaluate infants with diarrhea to rule out infectious, allergic, or anatomical causes before considering CODEs as the underlying etiology. Diagnostic investigations for CODEs encompass various modalities, including stool tests, blood tests, immunological studies, endoscopy and biopsies for histology and electron microscopy, and next-generation sequencing (NGS). NGS plays a pivotal role in identifying the genetic mutations responsible for CODEs. Treatment options for CODEs are limited, often relying on total parenteral nutrition for hydration and nutritional support. In severe cases, intestinal transplantation may be considered. The long-term prognosis varies among specific CODEs, with some patients experiencing ongoing intestinal failure and associated complications. In conclusion, the early recognition and accurate diagnosis of CODEs are of paramount importance for implementing appropriate management strategies. Further research and advancements in genetic testing hold promise for enhancing diagnostic accuracy and exploring potential targeted therapies for these rare genetic disorders.


Diarrhea , Malabsorption Syndromes , Humans , Diarrhea/therapy , Diarrhea/etiology , Diarrhea/congenital , Malabsorption Syndromes/therapy , Malabsorption Syndromes/diagnosis , Malabsorption Syndromes/genetics , Infant, Newborn , Infant , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/therapy , Metabolism, Inborn Errors/genetics , Mucolipidoses/diagnosis , Mucolipidoses/therapy , Mucolipidoses/genetics , Microvilli/pathology , Intestinal Diseases/diagnosis , Intestinal Diseases/therapy , Intestinal Diseases/genetics , Abnormalities, Multiple , Diarrhea, Infantile
4.
J Clin Invest ; 133(20)2023 10 16.
Article En | MEDLINE | ID: mdl-37643022

Microvillus inclusion disease (MVID), caused by loss-of-function mutations in the motor protein myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid/base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of Na+/H+ exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel-blocking antidiarrheal drug crofelemer dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. γ-Secretase inhibition with DAPT recovered apical brush border structure and functional Na+/H+ exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum/glucocorticoid-regulated kinase 2 (SGK2) and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID.


Malabsorption Syndromes , Mucolipidoses , Myosin Type V , Humans , Microvilli/genetics , Myosin Heavy Chains/genetics , Myosin Type V/genetics , Enterocytes/metabolism , Malabsorption Syndromes/genetics , Malabsorption Syndromes/therapy , Malabsorption Syndromes/metabolism , Mucolipidoses/genetics , Mucolipidoses/therapy , Mucolipidoses/metabolism
5.
Pediatr Dev Pathol ; 26(4): 406-410, 2023.
Article En | MEDLINE | ID: mdl-37278357

Inherited syndromes of congenital enteropathy are rare, with many genetic causes described. Mutations of the AP1S1 gene results in the syndrome of intellectual disability, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (IDEDNIK, formerly in the medical literature as MEDNIK). The clinicopathologic features of the enteropathy in IDEDNIK syndrome have not been fully explored. We describe a female infant who presented with metabolic acidosis, lethargy, and 14 watery stools per day. In the intensive care unit she required parenteral nutrition. She was found to have a novel homozygous pathogenic variant in the AP1S1 gene c.186T>G (p.Y62*). Esophagogastroduodenoscopy and colonoscopy at 6 months of age were grossly normal. However, histologic sections of the duodenum showed mild villous blunting and enterocytes with cytoplasmic vacuoles. CD10 immunostaining highlighted the disrupted brush border. MOC31 immunostaining was wild-type with a membranous pattern of expression. Electron microscopy of the duodenum showed scattered enterocytes cells with shortened and disrupted apical microvilli. Although there is a mixed gap diarrhea and disrupted brush border, there are no significant inclusions typical of microvillus inclusion disease, nor tufted enterocytes typical of tufting enteropathy, making the clinical and histopathologic features for this syndrome unique.


Adaptor Protein Complex sigma Subunits , Malabsorption Syndromes , Female , Humans , Infant , Adaptor Protein Complex 1/genetics , Adaptor Protein Complex sigma Subunits/genetics , Diarrhea/genetics , Duodenum , Malabsorption Syndromes/diagnosis , Malabsorption Syndromes/genetics , Malabsorption Syndromes/metabolism , Mutation , Syndrome
6.
Cell Mol Gastroenterol Hepatol ; 14(2): 295-310, 2022.
Article En | MEDLINE | ID: mdl-35421597

BACKGROUND & AIMS: UNC45A is a myosin (co-)chaperone, and mutations in the UNC45A gene were recently identified in osteo-oto-hepato-enteric (O2HE) syndrome patients presenting with congenital diarrhea and intrahepatic cholestasis. Congenital diarrhea and intrahepatic cholestasis are also the prime symptoms in patients with microvillus inclusion disease (MVID) and mutations in MYO5B, encoding the recycling endosome-associated myosin Vb. The aim of this study was to determine whether UNC45A and myosin Vb are functionally linked. METHODS: CRISPR-Cas9 gene editing and site-directed mutagenesis were performed with intestinal epithelial and hepatocellular cell lines, followed by Western blotting, quantitative polymerase chain reaction, and scanning electron and/or confocal fluorescence microscopy to determine the relationship between (mutants of) UNC45A and myosin Vb. RESULTS: UNC45A depletion in intestinal and hepatic cells reduced myosin Vb protein expression, and in intestinal epithelial cells, it affected 2 myosin Vb-dependent processes that underlie MVID pathogenesis: rat sarcoma-associated binding protein (RAB)11A-positve recycling endosome positioning and microvilli development. Reintroduction of UNC45A in UNC45A-depleted cells restored myosin Vb expression, and reintroduction of UNC45A or myosin Vb, but not the O2HE patient UNC45A-c.1268T>A variant, restored recycling endosome positioning and microvilli development. The O2HE patient-associated p.V423D substitution, encoded by the UNC45A-c.1268T>A variant, impaired UNC45A protein stability but as such not the ability of UNC45A to promote myosin Vb expression and microvilli development. CONCLUSIONS: A functional relationship exists between UNC45A and myosin Vb, thereby connecting 2 rare congenital diseases with overlapping enteropathy at the molecular level. Protein instability rather than functional impairment underlies the pathogenicity of the O2HE syndrome-associated UNC45A-p.V423D mutation.


Cholestasis, Intrahepatic , Diarrhea , Intracellular Signaling Peptides and Proteins , Malabsorption Syndromes , Mucolipidoses , Myosin Type V , Cholestasis, Intrahepatic/genetics , Diarrhea/congenital , Diarrhea/genetics , Enterocytes/metabolism , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Malabsorption Syndromes/genetics , Microvilli/pathology , Mucolipidoses/genetics , Myosin Heavy Chains/genetics , Myosin Heavy Chains/metabolism , Myosin Type V/genetics , Myosin Type V/metabolism , Myosins/metabolism , Rare Diseases
7.
Vitam Horm ; 119: 241-274, 2022.
Article En | MEDLINE | ID: mdl-35337622

Vitamin B12 is assimilated and transported by complex mechanisms that involve three transport proteins, intrinsic factor (IF), haptocorrin (HC) and transcobalamin (TC) and their respective membrane receptors. Vitamin deficiency is mainly due to inadequate dietary intake in vegans, and B12 malabsorption is related to digestive diseases. This review explores the physiology of vitamin B12 absorption and the mechanisms and diseases that produce malabsorption. In the stomach, B12 is released from food carrier proteins and binds to HC. The degradation of HC by pancreatic proteases and the pH change trigger the transfer of B12 to IF in the duodenum. Cubilin and amnionless are the two components of the receptor that mediates the uptake of B12 in the distal ileum. Part of liver B12 is excreted in bile, and undergoes an enterohepatic circulation. The main causes of B12 malabsorption include inherited disorders (Intrinsic factor deficiency, Imerslund-Gräsbeck disease, Addison's pernicious anemia, obesity, bariatric surgery and gastrectomies. Other causes include pancreatic insufficiency, obstructive Jaundice, tropical sprue and celiac disease, bacterial overgrowth, parasitic infestations, Zollinger-Ellison syndrome, inflammatory bowel diseases, chronic radiation enteritis of the distal ileum and short bowel. The assessment of B12 deficit is recommended in the follow-up of subjects with bariatric surgery. The genetic causes of B12 malabsorption are probably underestimated in adult cases with B12 deficit. Despite its high prevalence in the general population and in the elderly, B12 malabsorption cannot be anymore assessed by the Schilling test, pointing out the urgent need for an equivalent reliable test.


Anemia, Megaloblastic , Malabsorption Syndromes , Vitamin B 12 Deficiency , Adult , Aged , Anemia, Megaloblastic/complications , Anemia, Megaloblastic/genetics , Humans , Intrinsic Factor , Malabsorption Syndromes/complications , Malabsorption Syndromes/genetics , Malabsorption Syndromes/metabolism , Male , Vitamin B 12/metabolism , Vitamin B 12 Deficiency/etiology , Vitamin B 12 Deficiency/metabolism
9.
Prenat Diagn ; 42(1): 136-140, 2022 Jan.
Article En | MEDLINE | ID: mdl-34816459

BACKGROUNDS: Microvillus inclusion disease (MVID) characterizes as intractable life-threatening watery diarrhea malnutrition after birth. MATERIALS & METHODS: Here we describe two patients with prenatal ultrasound findings of bowel dilation or increased amniotic fluid volume presented intractable diarrhea after birth. Exome sequencing and Intestinal biopsy were performed for the patients and their parents to reveal the underlying causes. The mutations were verified by Sanger sequencing and quantitative polymerase chain reaction. RESULTS: Exome sequencing revealed that both of the patients carrying MYO5B compound heterozygote mutations that were inherited from their parents. CONCLUSION: Here we describe two cases with MVID caused by MYO5B deficiency, which was the most common caused with prenatal ultrasound findings of bowel dilation and increased amniotic fluid volume. Due to the lack of effective curative therapies, early diagnosis even in prenatal of MVID can provide parents with better genetic counseling on the fetal prognosis.


Malabsorption Syndromes/etiology , Microvilli/pathology , Mucolipidoses/etiology , Myosin Heavy Chains/deficiency , Myosin Type V/deficiency , Female , Gestational Age , Humans , Infant, Newborn , Malabsorption Syndromes/genetics , Male , Microvilli/genetics , Mucolipidoses/genetics , Mutation/genetics , Myosin Heavy Chains/genetics , Myosin Type V/genetics , Noninvasive Prenatal Testing/methods , Ultrasonography, Prenatal/methods , Exome Sequencing/methods
10.
BMC Pediatr ; 21(1): 449, 2021 10 11.
Article En | MEDLINE | ID: mdl-34629076

BACKGROUND: Chylomicron retention disease (Anderson disease) is a result for variant of the SAR1B gene. It is a rare autosomal recessive hereditary disorder with most incidence in infant. It is characterized by lipid malabsorption syndrome with fatty, chronic diarrhea, and growth retardation. CASE PRESENTATION: We report a case of a 19-month Syrian boy who presented with vomiting, growth failure, and chronic, fatty diarrhea. Upper gastrointestinal endoscopy showed whitish appearing duodenal mucosa and small intestinal biopsies revealed steatosis of enterocytes. Genetic testing confirmed chylomicron retention disease with the first description of variant located in the fourth helix of sar1b protein. The patient is treated with nutritional supplements and fat-soluble vitamin supplementation resulting in significant improvement. CONCLUSION: Early endoscopy is recommended in infants with persistent vomiting and failure to thrive due to high suspicion for a disorder of hypocholesterolemia. Early diagnosis and treatment are essential to avoid serious clinical complications, especially neurological impairment.


Hypobetalipoproteinemias , Malabsorption Syndromes , Monomeric GTP-Binding Proteins , Humans , Infant , Malabsorption Syndromes/diagnosis , Malabsorption Syndromes/genetics , Male , Monomeric GTP-Binding Proteins/metabolism , Syria
11.
J Endocrinol ; 252(1): 31-44, 2021 11 24.
Article En | MEDLINE | ID: mdl-34647524

Changes in dietary habits have occurred concomitantly with a rise of type 2 diabetes (T2D) and obesity. Intestine is the first organ facing nutrient ingestion and has to adapt its metabolism with these dietary changes. HNF-4γ, a transcription factor member of the nuclear receptor superfamily and mainly expressed in intestine, has been suggested to be involved in susceptibility to T2D. Our aim was to investigate the role of HNF-4γ in metabolic disorders and related mechanisms. Hnf4g-/- mice were fed high-fat/high-fructose (HF-HF) diet for 6 weeks to induce obesity and T2D. Glucose homeostasis, energy homeostasis in metabolic cages, body composition and stool energy composition, as well as gene expression analysis in the jejunum were analyzed. Despite an absence of decrease in calorie intake, of increase in locomotor activity or energy expenditure, Hnf4g-/- mice fed with HF-HF are protected against weight gain after 6 weeks of HF-HF diet. We showed that Hnf4g-/- mice fed HF-HF display an increase in fecal calorie loss, mainly due to intestinal lipid malabsorption. Gene expression of lipid transporters, Fatp4 and Scarb1 and of triglyceride-rich lipoprotein secretion proteins, Mttp and ApoB are decreased in gut epithelium of Hnf4g-/- mice fed HF-HF, showing the HNF-4γ role in intestine lipid absorption. Furthermore, plasma GLP-1 and jejunal GLP-1 content are increased in Hnf4g-/- mice fed HF-HF, which could contribute to the glucose intolerance protection. The loss of HNF-4γ leads to a protection against a diet-induced weight gain and to a deregulated glucose homeostasis, associated with lipid malabsorption.


Hepatocyte Nuclear Factor 4/genetics , Intestinal Absorption/genetics , Lipid Metabolism/genetics , Obesity/genetics , Animals , Cells, Cultured , Diet, High-Fat/adverse effects , Female , Fructose/adverse effects , Gene Deletion , Glucose Intolerance/etiology , Glucose Intolerance/genetics , Glucose Intolerance/metabolism , Intestines/metabolism , Malabsorption Syndromes/genetics , Malabsorption Syndromes/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Obesity/etiology , Obesity/metabolism , Triglycerides/metabolism , Weight Gain/genetics
12.
Indian J Pediatr ; 88(11): 1135-1138, 2021 Nov.
Article En | MEDLINE | ID: mdl-34292522

Congenital diarrhea and enteropathies (CODEs) are monogenic disorders causing early onset of intractable diarrhea. Their diagnosis and management are challenging. With the availability of commercial next generation genetic testing, we are now better able to classify and manage these disorders. The authors present their experience with 4 cases. Two patients had congenital tufting enteropathy (CTE) and 1 case each of microvillous inclusion disease (MVID) and trichohepatoenteric syndrome (THES). Age at onset varied from 3 to 38 d of life. Light microscopy and electron microscopy of duodenal and rectal endoscopic biopsies were consistent with the diagnosis. Genetic evaluation was possible in 3 cases indicating causative mutations. Two children (CTE and MVID) were alive at last follow-up. The authors suggest a stepwise approach to the diagnosis and management of these disorders in the Indian context.


Diarrhea, Infantile , Intestinal Diseases , Malabsorption Syndromes , Mucolipidoses , Child , Diarrhea/diagnosis , Diarrhea/etiology , Diarrhea, Infantile/diagnosis , Humans , Infant , Malabsorption Syndromes/diagnosis , Malabsorption Syndromes/genetics
13.
JCI Insight ; 6(16)2021 08 23.
Article En | MEDLINE | ID: mdl-34197342

Functional loss of myosin Vb (MYO5B) induces a variety of deficits in intestinal epithelial cell function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). The impact of MYO5B loss on differentiated cell lineage choice has not been investigated. We quantified the populations of differentiated epithelial cells in tamoxifen-induced, epithelial cell-specific MYO5B-knockout (VilCreERT2 Myo5bfl/fl) mice utilizing digital image analysis. Consistent with our RNA-sequencing data, MYO5B loss induced a reduction in tuft cells in vivo and in organoid cultures. Paneth cells were significantly increased by MYO5B deficiency along with expansion of the progenitor cell zone. We further investigated the effect of lysophosphatidic acid (LPA) signaling on epithelial cell differentiation. Intraperitoneal LPA significantly increased tuft cell populations in both control and MYO5B-knockout mice. Transcripts for Wnt ligands were significantly downregulated by MYO5B loss in intestinal epithelial cells, whereas Notch signaling molecules were unchanged. Additionally, treatment with the Notch inhibitor dibenzazepine (DBZ) restored the populations of secretory cells, suggesting that the Notch pathway is maintained in MYO5B-deficient intestine. MYO5B loss likely impairs progenitor cell differentiation in the small intestine in vivo and in vitro, partially mediated by Wnt/Notch imbalance. Notch inhibition and/or LPA treatment may represent an effective therapeutic approach for treatment of MVID.


Malabsorption Syndromes/genetics , Microvilli/pathology , Mucolipidoses/genetics , Myosin Type V/deficiency , Receptors, Notch/metabolism , Wnt Signaling Pathway/genetics , Animals , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cells, Cultured , Dibenzazepines/pharmacology , Disease Models, Animal , Enterocytes/drug effects , Enterocytes/metabolism , Humans , Intestinal Mucosa/cytology , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Jejunum/cytology , Jejunum/drug effects , Jejunum/pathology , Lysophospholipids/pharmacology , Lysophospholipids/therapeutic use , Malabsorption Syndromes/drug therapy , Malabsorption Syndromes/pathology , Mice , Mice, Knockout , Microvilli/genetics , Mucolipidoses/drug therapy , Mucolipidoses/pathology , Myosin Type V/genetics , Organoids , Primary Cell Culture , Receptors, Notch/antagonists & inhibitors , Stem Cells/physiology , Wnt Signaling Pathway/drug effects
14.
Front Endocrinol (Lausanne) ; 12: 664839, 2021.
Article En | MEDLINE | ID: mdl-34122338

Background: Malabsorption of levothyroxine (LT4) is a common problem faced in clinical practice. It is usually solved, if there are no complexities including gastrointestinal absorption disorder, by taking medicines on an empty stomach and avoiding foods interfering with LT4. Herein we present a rare case of a patient exhibiting malabsorption of LT4 with decreased membranous expression of ileal transporters. Case: The 22-Year-old female presented with sustained hypothyroid status despite medication of 7.8 µg/kg LT4. Medical history and LT4 absorption test (the absorption rate 8.4%) excluded pseudomalabsorption. No organic gastrointestinal disorder was found in the patient by blood chemistry, endoscopies, and abdominal computed tomography scan. The immunohistochemical analysis showed decreased membranous expression of LAT1 and LAT2 in distal ileum and ascending colon in the patient compared to 20 controls who have no thyroid disease. The expression of MCT8 in colon appeared at both nucleus and brush border in the patient, while it was limited to brush border in controls. The expression of other transporters was similar between the patient and controls. Conclusion: The changes of the expression of LAT1 and LAT2 in this patient showing LT4 malabsorption might help to understand the role of intestinal transporters in the absorption of LT4 in humans. The functional relevance of the decrement of LAT1 and LAT2 in this patient remains to be elucidated.


Adaptor Proteins, Signal Transducing/metabolism , Hypothyroidism/drug therapy , Large Neutral Amino Acid-Transporter 1/metabolism , Malabsorption Syndromes/diagnosis , Thyroxine/pharmacokinetics , Adaptor Proteins, Signal Transducing/genetics , Adult , Case-Control Studies , Female , Humans , Hypothyroidism/metabolism , Hypothyroidism/pathology , Large Neutral Amino Acid-Transporter 1/genetics , Malabsorption Syndromes/genetics , Malabsorption Syndromes/metabolism , Prognosis , Thyroxine/therapeutic use , Tissue Distribution , Young Adult
15.
J Pediatr Gastroenterol Nutr ; 72(6): 826-832, 2021 06 01.
Article En | MEDLINE | ID: mdl-33976085

OBJECTIVES: Congenital diarrhea and enteropathies linked to epithelial structural abnormalities constitute 3 different rare diseases: the tufting enteropathies (TE; EPCAM and SPINT2 mutations), microvillous inclusion disease (MVID; MYO5B and STX3 mutations), and tricho-hepato-enteric syndrome (THE; TTC37 and SKIV2L mutations). Moreover, enteroendocrine deficiencies (ED; PCSK1 and NEUROG3 mutations) share common clinical characteristics with TE, THE, and MVID in that the treatment requires, in most cases, long-term parenteral nutrition. Although numerous cases have been reported in the literature, aggregated data on morbidity and mortality are missing owing to the rarity of the diseases. METHODS: We performed a systematic review of all published cases and retrieved 86 articles describing 323 patients (164 boys and 135 girls). RESULTS: The mortality rate was 20.28%, with a median age at death of 13.5 months (range 0-228 months); the mortality risk was 30.8/1000 person-year; in half of the cases, death was caused by infections. Parenteral nutrition was required in 95.4% of patients and weaning off from parenteral nutrition was achieved in 29.35% at a median age of 23 months (range 3.3-276 months). The patients with ED linked to PCSK1 were nearly all weaned at a median age of 14 months, but most of the patients became overweight. MVID patients with MYO5B mutations were most often born preterm. ED linked to NEUROG3 mutation and THE patients usually presented with intrauterine growth retardation. CONCLUSIONS: This review presents data from 323 patients with congenital diarrhea linked to EPCAM TE, SPINT2 TE, TTC37 THE, SKIV2L THE, MYO5B MVID, STX3 MVID, NEUROG3 ED, and PCSK1 ED mutations.


Diarrhea, Infantile , Intestinal Diseases , Malabsorption Syndromes , Mucolipidoses , Female , Humans , Infant , Infant, Newborn , Malabsorption Syndromes/genetics , Male , Membrane Glycoproteins , Microvilli
16.
Am J Med Genet A ; 185(10): 2873-2877, 2021 10.
Article En | MEDLINE | ID: mdl-34037310

Trichohepatoenteric syndrome (THES) is a very rare autosomal recessive genetic disorder, which is characterized by intractable diarrhea during infancy, dysmorphic features, immunodeficiency, and a failure to thrive. There are still significant difficulties for patients and clinicians in terms of the management of THES, even though its molecular basis has been uncovered in the last decade. In this article, we have presented two cases relating to siblings that have been diagnosed with the condition. Concerning one of the patients, we described a novel variation (c.2114 + 5G > A) in the TTC37 gene and a mild clinical course; meanwhile, the other one was clinically diagnosed with THES at 17 years of age, but they had seizures and died suddenly. These cases expand the spectrum of clinical findings in relation to THES.


Carrier Proteins/genetics , Diarrhea, Infantile/genetics , Failure to Thrive/genetics , Fetal Growth Retardation/genetics , Hair Diseases/genetics , Malabsorption Syndromes/genetics , Microvilli/pathology , Mucolipidoses/genetics , Adolescent , Diarrhea, Infantile/complications , Diarrhea, Infantile/diagnosis , Diarrhea, Infantile/pathology , Facies , Failure to Thrive/complications , Failure to Thrive/diagnosis , Failure to Thrive/pathology , Female , Fetal Growth Retardation/diagnosis , Fetal Growth Retardation/pathology , Genetic Predisposition to Disease , Hair Diseases/complications , Hair Diseases/diagnosis , Hair Diseases/pathology , Humans , Infant , Malabsorption Syndromes/complications , Malabsorption Syndromes/diagnosis , Malabsorption Syndromes/pathology , Male , Microvilli/genetics , Mucolipidoses/complications , Mucolipidoses/diagnosis , Mucolipidoses/pathology , Primary Immunodeficiency Diseases/complications , Primary Immunodeficiency Diseases/diagnosis , Primary Immunodeficiency Diseases/genetics , Primary Immunodeficiency Diseases/pathology , Siblings
17.
Hum Genet ; 140(8): 1143-1156, 2021 Aug.
Article En | MEDLINE | ID: mdl-33974130

Biallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic-intestinal and retinal-disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.


Eye Diseases, Hereditary/genetics , Intestinal Mucosa/metabolism , Malabsorption Syndromes/genetics , Microvilli/pathology , Mucolipidoses/genetics , Polymorphism, Single Nucleotide , Qa-SNARE Proteins/genetics , Retinal Cone Photoreceptor Cells/metabolism , Retinal Dystrophies/genetics , Aged , Aged, 80 and over , Alcohol Oxidoreductases/genetics , Alcohol Oxidoreductases/metabolism , Animals , Autopsy , Co-Repressor Proteins/genetics , Co-Repressor Proteins/metabolism , Eye Diseases, Hereditary/metabolism , Eye Diseases, Hereditary/pathology , Female , Gene Expression Regulation , Homozygote , Humans , Intestinal Mucosa/pathology , Malabsorption Syndromes/metabolism , Malabsorption Syndromes/pathology , Mice , Mice, Knockout , Microvilli/genetics , Microvilli/metabolism , Mucolipidoses/metabolism , Mucolipidoses/pathology , Phenotype , Qa-SNARE Proteins/deficiency , RNA, Messenger/genetics , RNA, Messenger/metabolism , Retinal Cone Photoreceptor Cells/pathology , Retinal Dystrophies/metabolism , Retinal Dystrophies/pathology , Sensory Rhodopsins/genetics , Sensory Rhodopsins/metabolism , Exome Sequencing
19.
Am J Surg Pathol ; 45(8): 1091-1097, 2021 08 01.
Article En | MEDLINE | ID: mdl-33756496

Congenital tufting enteropathy (CTE) is a rare heritable cause of intractable diarrhea due to EPCAM mutation. Pathologic findings include intestinal villous atrophy, tufted discohesive tear-drop-shaped epithelium, and a normal brush border. In affected patients, absent intestinal epithelial cell adhesion molecule (EpCAM) expression results in loss of MOC31 immunostaining. CTE liver pathology has not yet been described. We identified CTE patients with liver biopsies and reviewed clinicopathologic material including MOC31 immunohistochemistry. Three CTE patients had 4 liver core biopsies (at ages 1, 5, 7, and 16 y), 2 for preintestinal transplant evaluation, and 2 (from a single patient) for pretreatment assessment of chronic hepatitis C; all had received parenteral nutrition (PN). All samples showed loss of biliary epithelial polarization and mild portal and lobular inflammation. Only the hepatitis C patient demonstrated fibrosis. One patient each had lobular neutrophilic microabscesses and macrovesicular steatosis. Proliferative ductular reactions were absent in CTE patients but present in all controls on PN for other reasons. MOC31 was absent in biliary epithelium and hepatocytes of all CTE patients; controls showed consistent strong membranous biliary epithelial and patchy membranous periportal hepatocyte staining. Our data show that, histologically, hepatopathy in CTE can be difficult to separate from comorbid disease including PN effect; however, the absent ductular reaction may be characteristic. MOC31 localization in the biliary epithelium and zone 1 hepatocytes of controls suggests these compartments of the liver might be most susceptible to effects of EpCAM deficiency. In addition, we validate the liver as suitable tissue for CTE diagnosis using MOC31 immunohistochemistry.


Diarrhea, Infantile/complications , Liver Diseases/etiology , Liver Diseases/pathology , Malabsorption Syndromes/complications , Adolescent , Child , Child, Preschool , Diarrhea, Infantile/genetics , Epithelial Cell Adhesion Molecule/genetics , Female , Humans , Immunohistochemistry , Infant , Liver/pathology , Malabsorption Syndromes/genetics , Male
20.
Physiol Rep ; 9(3): e14733, 2021 02.
Article En | MEDLINE | ID: mdl-33527741

Bile acids are natural detergents that aid in the absorption of dietary lipids. Fatty acid binding protein 6 (Fabp6) is a component of the bile acid recovery system that operates in the small intestine. The aim of this study was to determine if Fabp6 deficiency causes dietary fat malabsorption. Wild-type and Fabp6-deficient mice were fed a Western-style diet (WSD) or a reference low-fat diet (LFD) for 10 weeks. The body weight gain, bile acid excretion, fat excretion, energy metabolism, and major gut microbial phyla of the mice were assessed at the end of the controlled diet period. Fabp6-/- mice exhibited enhanced excretion of both bile acids and fat on the WSD but not on the LFD diet. Paradoxically, male Fabp6-/- mice, but not female Fabp6-/- mice, had greater adiposity despite increased fat excretion. Analysis of energy intake and of expenditure by indirect calorimetry revealed sex differences in physical activity level and respiratory quotient, but these did not account for the enhanced adiposity displayed by male Fabp6-/- mice. Analysis of stool DNA showed sex-specific changes in the abundance of major phyla of bacteria in response to Fabp6 deficiency and WSD feeding. The results obtained indicate that the malabsorption of bile acids that occurs in Fabp6-/- mice is associated with dietary fat malabsorption on the high-fat diet but not on the low-fat diet. The WSD induced a sexually dimorphic increase in adiposity displayed by Fabp6-/- mice and sexually distinct pattern of change in gut microbiota composition.


Adiposity , Diet, Western/adverse effects , Fatty Acid-Binding Proteins/deficiency , Gastrointestinal Microbiome , Intestinal Absorption , Lipid Metabolism , Malabsorption Syndromes/metabolism , Animals , Bile Acids and Salts/metabolism , Dysbiosis , Energy Metabolism , Fatty Acid-Binding Proteins/genetics , Female , Genotype , Malabsorption Syndromes/genetics , Malabsorption Syndromes/microbiology , Male , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Sex Characteristics , Sex Factors , Weight Gain
...