ABSTRACT
La clorhidrorrea congénita es un trastorno genético infrecuente pero importante caracterizado por una alteración grave del balance hidroelectrolítico como resultado de un defecto en la absorción intestinal de cloruros. Los niños afectados presentan diarrea persistente, deshidratación y malnutrición; el control médico y del desarrollo son complejos. Mejorar la detección prenatal es esencial para facilitar la atención del paciente, las intervenciones tempranas y el asesoramiento genético informado. Sin embargo, a pesar de los avances de la medicina, la naturaleza compleja y la escasa frecuencia de esta entidad, constituyen un desafío para la detección prenatal. En este estudio, se reporta el caso de una embarazada donde los estudios por imágenes de resonancia magnética fetales identificaron en forma efectiva las características típicas de la clorhidrorrea congénita. Se proveen conocimientos sobre las complejidades del diagnóstico y se sugieren caminos para las estrategias de detección temprana de esta enfermedad.
Congenital chloride diarrhea (CCD) is a rare but significant genetic disorder characterized by severe electrolyte imbalances resulting from impaired intestinal chloride absorption. Affected children experience persistent diarrhea, dehydration, and malnutrition, complicating medical and developmental care. The enhancement of prenatal detection is crucial for improved patient management, early interventions, and informed genetic counseling. However, despite advancements in medicine, the complex nature and rarity of CCD make prenatal detection challenging. In this study, we report a fetal case where prenatal magnetic resonance imaging (MRI) effectively identified the distinctive characteristics of CCD, providing insights into the complexities of diagnosis and suggesting avenues for enhanced early detection strategies.
Subject(s)
Humans , Female , Pregnancy , Prenatal Diagnosis/methods , Diarrhea/congenital , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Diarrhea/etiology , Genetic CounselingABSTRACT
INTRODUCTION: Congenital chloride diarrhoea (CCD) is an autosomal recessive condition that causes secretory diarrhoea and potentially deadly electrolyte imbalances in infants because of solute carrier family 26 member 3 (SLC26A3) gene mutations. CASE PRESENTATION: A 7-month-old Chinese infant with a history of maternal polyhydramnios presented with frequent watery diarrhoea, severe dehydration, hypokalaemia, hyponatraemia, failure to thrive, metabolic alkalosis, hyperreninaemia, and hyperaldosteronaemia. Genetic testing revealed a compound heterozygous SLC26A3 gene mutation in this patient (c.269_270dup and c.2006 C > A). Therapy was administered in the form of oral sodium and potassium chloride supplements, which decreased stool frequency. CONCLUSIONS: CCD should be considered when an infant presents with prolonged diarrhoea during infancy, particularly in the context of maternal polyhydramnios and dilated foetal bowel loops.
Subject(s)
Diarrhea , Diarrhea/congenital , Metabolism, Inborn Errors , Mutation , Sulfate Transporters , Humans , Sulfate Transporters/genetics , Diarrhea/genetics , Infant , Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/diagnosis , Chloride-Bicarbonate Antiporters/genetics , Female , Heterozygote , Male , Polyhydramnios/genetics , Potassium Chloride/therapeutic use , Potassium Chloride/administration & dosage , East Asian PeopleABSTRACT
BACKGROUND: Congenital sucrase-isomaltase deficiency (CSID) is a rare inherited carbohydrate malabsorption disorder caused by sucrase-isomaltase (SI) gene variants. In CSID, an autosomal recessively inherited disease, symptoms can also be seen in individuals with heterozygous mutations. METHODS: The variant spectrum was evaluated retrospectively in individuals who presented with chronic diarrhea between 2014 and 2022 and had undergone genetic testing of the SI gene considering CSID due to diet-related complaints. RESULTS: Ten patients with chronic diarrhea were genetically evaluated with SI gene sequencing. In patients diagnosed with CSID and whose symptoms improved with enzyme replacement therapy, the genetic mutation zygosity was found to be heterozygous at a rate of 90%. In 10% of the patients, the mutation was homozygous. Limiting consuming sucrose and isomaltose foods reduced the patients' complaints, but the symptoms did not disappear completely. With the initiation of sacrosidase enzyme replacement therapy, the patient's complaints completely disappeared. CONCLUSION: In CSID, defined as an autosomal recessive disease, clinical symptoms can also be seen in heterozygous cases previously described as carriers, and these patients also benefit from sacrosidase enzyme replacement therapy. In light of these findings, the autosomal recessive definition of CSID does not fully characterize the disease.What is Known:CSID is a rare inherited carbohydrate malabsorption disorder caused by sucrase-isomaltase gene variants.In congenital sucrase-isomaltase deficiency, an autosomal recessively inherited disorder, symptoms can also be seen in individuals with heterozygous mutations.What is new:Severe disease symptoms can also be seen in heterozygous cases, which were thought to be carriers because the disease was previously described as autosomal recessive.Sacrosidase enzyme replacement therapy also eliminates the disease symptoms in patients with heterozygous CSID mutations.This is the second study on sucrase-isomaltase enzyme deficiency pediatric groups in Türkiye and Europe.
This is the study to evaluate the congenital sucrase-isomaltase enzyme deficiency in chronic diarrhea cases covering adults and childhood in our country and the clinical features and treatment response characteristics of the variants detected in these patients.In addition, another aim of our study is that sucraseisomaltase enzyme deficiency should be considered in the differential diagnosis and should be kept in mind, especially in cases with chronic diarrhea whose cause cannot be determined in childhood.
Subject(s)
Carbohydrate Metabolism, Inborn Errors , Diarrhea , Mutation , Sucrase-Isomaltase Complex , Humans , Sucrase-Isomaltase Complex/deficiency , Sucrase-Isomaltase Complex/genetics , Carbohydrate Metabolism, Inborn Errors/genetics , Carbohydrate Metabolism, Inborn Errors/diagnosis , Female , Male , Retrospective Studies , Child , Adolescent , Child, Preschool , Diarrhea/genetics , Diarrhea/congenital , Diarrhea/etiology , Enzyme Replacement Therapy , Heterozygote , Infant , Adult , Young Adult , Homozygote , Genetic TestingABSTRACT
Mutations in the Kunitz-type serine protease inhibitor HAI-2, encoded by SPINT2, are responsible for the pathogenesis of syndromic congenital sodium diarrhea (SCSD), an intractable secretory diarrhea of infancy. Some of the mutations cause defects in the functionally required Kunitz domain 1 and/or subcellular targeting signals. Almost all SCSD patients, however, harbor SPINT2 missense mutations that affect the functionally less important Kunitz domain 2. How theses single amino acid substitutions inactivate HAI-2 was, here, investigated by the doxycycline-inducible expression of three of these mutants in HAI-2-knockout Caco-2 human colorectal adenocarcinoma cells. Examining protein expressed from these HAI-2 mutants reveals that roughly 50% of the protein is synthesized as disulfide-linked oligomers that lose protease inhibitory activity due to the distortion of the Kunitz domains by disarrayed disulfide bonding. Although the remaining protein is synthesized as monomers, its glycosylation status suggests that the HAI-2 monomer remains in the immature, lightly glycosylated form, and is not converted to the heavily glycosylated mature form. Heavily glycosylated HAI-2 possesses full anti-protease activity and appropriate subcellular targeting signals, including the one embedded in the complex-type N-glycan. As predicted, these HAI-2 mutants cannot suppress the excessive prostasin proteolysis caused by HAI-2 deletion. The oligomerization and glycosylation defects have also been observed in a colorectal adenocarcinoma line that harbors one of these SPINT2 missense mutations. Our study reveals that the abnormal protein folding and N-glycosylation can cause widespread HAI-2 inactivation in SCSD patents.
Subject(s)
Adenocarcinoma , Colorectal Neoplasms , Serine Endopeptidases , Humans , Membrane Glycoproteins/metabolism , Caco-2 Cells , Glycosylation , Mutation , Diarrhea/congenital , Protein Folding , Colorectal Neoplasms/genetics , Disulfides , Proteinase Inhibitory Proteins, Secretory/geneticsABSTRACT
Chronic diarrhea presents a significant challenge for managing nutritional and electrolyte deficiencies, especially in children, given the higher stakes of impacting growth and developmental consequence. Congenital secretory diarrhea (CSD) compounds this further, particularly in the case of the activating variants of the guanylate-cyclase 2C (GUCY2C) gene. GUCY2C encodes for the guanylate-cyclase 2C (GC-C) receptor that activates the downstream cystic fibrosis transmembrane receptor (CFTR) that primarily drives the severity of diarrhea with an unclear extent of influence on other intestinal channels. Thus far, management for CSD primarily consists of mitigating nutritional, electrolyte, and volume deficiencies with no known pathophysiology-driven treatments. For activating variants of GUCY2C, experimental compounds have shown efficacy in vitro for direct inhibition of GC-C but are not currently available for clinical use. However, Crofelemer, a CFTR inhibitory modulator with negligible systemic absorption, can theoretically help to treat this type of CSD. Herein, we describe and characterize the clinical course of a premature male infant with a de novo missense variant of GUCY2C not previously reported and highly consistent with CSD. With multi-disciplinary family-directed decision-making, a treatment for CSD was evaluated for the first time to our knowledge with Crofelemer.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator , Cystic Fibrosis , Child , Humans , Male , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Diarrhea/genetics , Diarrhea/therapy , Diarrhea/congenital , Intestines , Electrolytes/therapeutic use , Disease Progression , Receptors, EnterotoxinABSTRACT
Biallelic SPINT2 pathogenic variants cause a syndromic form of congenital diarrhea and enteropathy (OMIM 270420). To date, 35 patients have been reported and all presented with additional extra-intestinal features, apart from one case. We report on a 5-year-old girl who presented early in life with diarrhea and was found to have a novel homozygous variant in SPINT2. Pathological studies confirmed tufting enteropathy, and during her 5 years of life, she has not developed any extra-intestinal features. Molecular analysis detected a homozygous variant (NM_021102.4: c.203A>G (p. [Tyr68Cys]) in SPINT2. This is the first missense variant reported in the first Kunitz domain (KD1) of SPINT2 in humans. In vitro functional studies of this variant confirmed the deleterious effect leading to the loss of inhibitory activity of the intestinal serine proteases. This is the first description of SPINT2-related diarrhea in a patient who lived without long-term total parenteral nutrition. This study expands the clinical and molecular characteristics of SPINT2-related conditions.
Subject(s)
Diarrhea , Membrane Glycoproteins , Humans , Female , Child, Preschool , Membrane Glycoproteins/genetics , Diarrhea/genetics , Diarrhea/congenital , Intestines , Mutation, Missense/genetics , Serine EndopeptidasesABSTRACT
Congenital chloride diarrhea (CCD) is a rare but significant genetic disorder characterized by severe electrolyte imbalances resulting from impaired intestinal chloride absorption. Affected children experience persistent diarrhea, dehydration, and malnutrition, complicating medical and developmental care. The enhancement of prenatal detection is crucial for improved patient management, early interventions, and informed genetic counseling. However, despite advancements in medicine, the complex nature and rarity of CCD make prenatal detection challenging. In this study, we report a fetal case where prenatal magnetic resonance imaging (MRI) effectively identified the distinctive characteristics of CCD, providing insights into the complexities of diagnosis and suggesting avenues for enhanced early detection strategies.
La clorhidrorrea congénita es un trastorno genético infrecuente pero importante caracterizado por una alteración grave del balance hidroelectrolítico como resultado de un defecto en la absorción intestinal de cloruros. Los niños afectados presentan diarrea persistente, deshidratación y malnutrición; el control médico y del desarrollo son complejos. Mejorar la detección prenatal es esencial para facilitar la atención del paciente, las intervenciones tempranas y el asesoramiento genético informado. Sin embargo, a pesar de los avances de la medicina, la naturaleza compleja y la escasa frecuencia de esta entidad, constituyen un desafío para la detección prenatal. En este estudio, se reporta el caso de una embarazada donde los estudios por imágenes de resonancia magnética fetales identificaron en forma efectiva las características típicas de la clorhidrorrea congénita. Se proveen conocimientos sobre las complejidades del diagnóstico y se sugieren caminos para las estrategias de detección temprana de esta enfermedad.
Subject(s)
Diarrhea/congenital , Metabolism, Inborn Errors , Prenatal Diagnosis , Pregnancy , Child , Female , Humans , Prenatal Diagnosis/methods , Diarrhea/etiology , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Genetic CounselingABSTRACT
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.
Subject(s)
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, InfantileABSTRACT
A male infant with prenatal history significant for polyhydramnios requiring multiple amnioreductions with suspicion of small bowel atresia was born at 31 weeks 5 days' gestation with abdominal distension. He underwent three exploratory laparotomies and ileostomy for small bowel obstruction and was found to have fluid-filled intestinal dilatation. Serum and stool chemistries suggested sodium secretory diarrhoea. A rapid whole-exome sequencing confirmed de novo guanylate cyclase mutation variant as a cause for his congenital sodium secretory diarrhoea. He required large volume of fluid and electrolyte replacement along with total parenteral nutrition. Several medications to restore normal sodium homeostasis by targeting molecular mechanisms and pathogenesis described in previous literature failed to decrease stool output and electrolyte loss. He was discharged home at 11 months of age on total parenteral nutrition and weekly iron therapy.
Subject(s)
Guanylate Cyclase , Intestinal Obstruction , Infant , Pregnancy , Female , Humans , Male , Diarrhea/genetics , Diarrhea/congenital , Intestinal Obstruction/drug therapy , Electrolytes , Sodium/therapeutic use , MutationABSTRACT
CONTEXT: Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism. With only 17 reported cases, the clinical and mutational spectra of this disease are far from complete. OBJECTIVE: To identify the underlying genetic etiology in 3 unrelated Thai patients who presented with early-onset malabsorptive diarrhea, endocrine abnormalities, and renal defects and to determine the pathogenicity of the newly identified pathogenic variants using luciferase reporter assays and western blot. METHODS: Three unrelated patients with congenital diarrhea were recruited. Detailed clinical and endocrinological features were obtained. Exome sequencing was performed to identify mutations and in vitro functional experiments including luciferase reporter assay were studied to validate their pathogenicity. RESULTS: In addition to malabsorptive diarrhea due to enteric anendocrinosis, IDDM, short stature, and delayed puberty, our patients also exhibited pituitary gland hypoplasia with multiple pituitary hormone deficiencies (Patient 1, 2, 3) and proximal renal tubulopathy (Patient 2, 3) that have not previously reported. Exome sequencing revealed that Patient 1 was homozygous for c.371C > G (p.Thr124Arg) while the other 2 patients were homozygous for c.284G > C (p.Arg95Pro) in NEUROG3. Both variants have never been previously reported. Luciferase reporter assay demonstrated that these 2 variants impaired transcriptional activity of NEUROG3. CONCLUSIONS: This study reported pituitary gland hypoplasia with multiple pituitary hormone deficiencies and proximal renal tubulopathy and 2 newly identified NEUROG3 loss-of-function variants in the patients with NEUROG3-associated syndrome.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Diabetes Mellitus, Type 1 , Humans , Basic Helix-Loop-Helix Transcription Factors/genetics , Nerve Tissue Proteins/genetics , Mutation , Diarrhea/genetics , Diarrhea/congenital , Phenotype , Pituitary HormonesABSTRACT
BACKGROUND: Congenital sodium diarrhea (CSD) is a rare enteropathy displaying both broad variability in clinical severity and genetic locus and allelic heterogeneity. Eleven CSD patients were reported so far with SLC9A3 variants that impair the function of the encoded intestinal sodium-proton exchanger 3 (NHE3). METHODS: We report a 4-year-old patient, born prematurely in the 35th week of gestation, with antenatal polyhydramnios and dilated intestinal loops, and with diarrhea of congenital onset, 2-6 times a day, and with polydipsia. She thrived age-appropriately under a normal family diet. Serum sodium levels were repeatedly normal but urinary sodium excretion was low. Exome sequencing revealed compound heterozygous variants in SLC9A3 as the likely cause of the congenital diarrhea. RESULTS: While exome sequencing did not reveal pathogenic or likely pathogenic variants in other genes that cause syndromic or non-syndromic forms of congenital and intractable diarrheas, we identified novel compound heterozygous variants in SLC9A3, a complex allele with two missense changes, NP_004165.2:p.[Ser331Leu;Val449Ile] and in-trans the missense variant p.(Phe451Ser). CONCLUSION: The clinical phenotype here appears to localize to the milder end of the known CSD spectrum, and the identified variants suggest that this is the twelfth patient reported to date with CSD due to mutations in SLC9A3.
Subject(s)
Abnormalities, Multiple , Metabolism, Inborn Errors , Abnormalities, Multiple/genetics , Diarrhea/congenital , Diarrhea/genetics , Diarrhea/pathology , Female , Humans , Metabolism, Inborn Errors/genetics , Pregnancy , SodiumABSTRACT
BACKGROUND Congenital chloride diarrhea (CCD) is an autosomal recessive disease that is usually diagnosed in early childhood. Mutations in the SLC26A3 gene have been attributed to the primary etiology of disease development. Patients with CCD usually present with electrolyte disturbances, metabolic alkalosis, and chronic diarrhea. Early diagnosis is essential to prevent long-term complications that often require genetic testing. Bartter syndrome is another congenital disorder that has clinical features similar to CCD, which might cause a delay in diagnosis in a few patients. CASE REPORT We describe the case of a 28-year-old man who was misdiagnosed as having Bartter syndrome when he was 5 months old based on the clinical features of hypokalemia, metabolic alkalosis, and a family history of Bartter syndrome. He had multiple admissions with diarrhea and was diagnosed with ulcerative colitis. Unfortunately, the course was complicated by renal failure, and the patient underwent a kidney transplant. Persistent metabolic alkalosis with diarrhea after transplantation was unusual in Bartter syndrome. Therefore, his primary diagnosis was challenged and suspicion of CCD was raised, which was confirmed by genetic testing. CONCLUSIONS CCD is a rare congenital disorder that requires high clinical suspicion and often a genetic test to confirm diagnosis. Here, we report a patient who was misdiagnosed as having Bartter syndrome until early adulthood owing to several misleading factors. We hope by reporting this case it will raise awareness about CCD in high-prevalence areas and the importance of early diagnosis to prevent serious complications.
Subject(s)
Alkalosis , Bartter Syndrome , Colitis, Ulcerative , Adult , Alkalosis/complications , Alkalosis/etiology , Bartter Syndrome/complications , Bartter Syndrome/diagnosis , Bartter Syndrome/genetics , Child, Preschool , Colitis, Ulcerative/complications , Colitis, Ulcerative/diagnosis , Diagnostic Errors , Diarrhea/congenital , Diarrhea/diagnosis , Humans , Infant , Male , Metabolism, Inborn ErrorsABSTRACT
BACKGROUND AND AIMS: Subjects with congenital chloride diarrhea (CLD; a defect in solute carrier family 26 member 3 (SLC26A3)) are prone to inflammatory bowel disease (IBD). We investigated fecal microbiota in CLD and CLD-associated IBD. We also tested whether microbiota is modulated by supplementation with the short-chain fatty acid butyrate. SUBJECTS AND METHODS: We recruited 30 patients with CLD for an observational 3-week follow-up study. Thereafter, 16 consented to oral butyrate substitution for a 3-week observational period. Fecal samples, collected once a week, were assayed for calprotectin and potential markers of inflammation, and studied by 16S ribosomal ribonucleic acid (rRNA) gene amplicon sequencing and compared to that of 19 healthy controls and 43 controls with Crohn's disease. Data on intestinal symptoms, diet and quality of life were collected. RESULTS: Patients with CLD had increased abundances of Proteobacteria, Veillonella, and Prevotella, and lower abundances of normally dominant taxa Ruminococcaceae and Lachnospiraceae when compared with healthy controls and Crohn´s disease. No major differences in fecal microbiota were found between CLD and CLD-associated IBD (including two with yet untreated IBD). Butyrate was poorly tolerated and showed no major effects on fecal microbiota or biomarkers in CLD. CONCLUSIONS: Fecal microbiota in CLD is different from that of healthy subjects or Crohn´s disease. Unexpectedly, no changes in the microbiota or fecal markers characterized CLD-associated IBD, an entity with high frequency among patients with CLD.
Subject(s)
Crohn Disease , Gastrointestinal Microbiome , Inflammatory Bowel Diseases , Microbiota , Biomarkers , Butyrates , Crohn Disease/microbiology , Diarrhea/congenital , Diarrhea/genetics , Feces/microbiology , Follow-Up Studies , Gastrointestinal Microbiome/genetics , Humans , Inflammatory Bowel Diseases/microbiology , Metabolism, Inborn Errors , Quality of Life , RNA, Ribosomal, 16S/geneticsABSTRACT
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.
Subject(s)
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 DiseasesABSTRACT
Congenital chloride losing diarrhoea (CCLD) is a rare disease caused by mutations in an intestinal chloride/bicarbonate ion exchange channel. Few reports describe CCLD in adults and none has described the impact of a parasitic infection on CCLD. Severe diarrhoea may result in hypokalaemia with QT interval prolongation. Treatment with antiemetics may further increase the QT interval. To raise awareness of this preventable complication, we describe the course of a woman in her 20s with CCLD who developed COVID-19 and a Blastocystis hominis infestation. Treatment with antiemetics and hypokalaemia resulted in prolongation of the QT interval to 640 ms. While, the QT interval normalised with discontinuation of antiemetics and electrolyte replacement, patients with CCLD must take precautions to prevent gastrointestinal infections. Regardless, whenever patients with CCLD present to hospital, the authors recommend monitoring the QT interval and avoiding medications that predispose to torsade de pointes.
Subject(s)
Antiemetics , Blastocystis hominis , COVID-19 Drug Treatment , Hypokalemia , Long QT Syndrome , Adult , Chlorides , Diarrhea/chemically induced , Diarrhea/complications , Diarrhea/congenital , Diarrhea/drug therapy , Electrocardiography , Female , Humans , Hypokalemia/complications , Long QT Syndrome/chemically induced , Long QT Syndrome/drug therapy , Metabolism, Inborn ErrorsABSTRACT
INTRODUCTION: Gain-of-function mutations in guanylyl cyclase C (GCC) result in persistent diarrhea with perinatal onset. We investigated a specific GCC inhibitor, SSP2518, for its potential to treat this disorder. METHODS: We investigated the effect of SSP2518 on GCC-mediated intracellular cyclic guanosine monophosphate (cGMP) levels and on GCC-mediated chloride secretion in intestinal organoids from 3 patients with distinct activating GCC mutations and from controls, with and without stimulation of GCC with heat-stable enterotoxin. RESULTS: Patient-derived organoids had significantly higher basal cGMP levels than control organoids, which were lowered by SSP2518 to levels found in control organoids. In addition, SSP2518 significantly reduced cGMP levels and chloride secretion in patient-derived and control organoids (P < 0.05 for all comparisons) after heat-stable enterotoxin stimulation. DISCUSSION: We reported in this study that the GCC inhibitor SSP2518 normalizes cGMP levels in intestinal organoids derived from patients with GCC gain-of-function mutations and markedly reduces cystic fibrosis transmembrane conductance regulator-dependent chloride secretion, the driver of persistent diarrhea.
Subject(s)
Abnormalities, Multiple/drug therapy , Abnormalities, Multiple/genetics , Diarrhea/congenital , Metabolism, Inborn Errors/drug therapy , Metabolism, Inborn Errors/genetics , Receptors, Enterotoxin/antagonists & inhibitors , Abnormalities, Multiple/metabolism , Cyclic GMP/metabolism , Diarrhea/drug therapy , Diarrhea/genetics , Diarrhea/metabolism , Gain of Function Mutation , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Metabolism, Inborn Errors/metabolism , Receptors, Enterotoxin/geneticsABSTRACT
Proprotein convertase 1/3 (PC1/3), encoded by the PCSK1 gene, is expressed in neuronal and (entero)endocrine cell types, where it cleaves and hence activates a number of protein precursors that play a key role in energy homeostasis. Loss-of-function mutations in PCSK1 cause a recessive complex endocrinopathy characterized by malabsorptive diarrhea and early-onset obesity. Despite the fact that neonatal malabsorptive diarrhea is observed in all patients, it has remained understudied. The aim of this study was to investigate the enteroendocrine pathologies in a male patient with congenital PCSK1 deficiency carrying the novel homozygous c.1034A>C (p.E345A) mutation. This patient developed malabsorptive diarrhea and metabolic acidosis within the first week of life, but rapid weight gain was observed after total parenteral nutrition, and he displayed high proinsulin levels and low adrenocorticotropin. In vitro analysis showed that the p.E345A mutation in PC1/3 resulted in a (near) normal autocatalytic proPC1/3 processing and only partially impaired PC1/3 secretion, but the processing of a substrate in trans was completely blocked. Immunohistochemical staining did not reveal changes in the proGIP/GIP and proglucagon/GLP-1 ratio in colonic tissue. Hence, we report a novel PCSK1 deficient patient who, despite neonatal malabsorptive diarrhea, showed a normal morphology in the small intestine.
Subject(s)
Diarrhea/congenital , Diarrhea/genetics , Endocrine System Diseases/genetics , Mutation/genetics , Proprotein Convertase 1/genetics , Cell Line , HEK293 Cells , Homozygote , Humans , Infant , Male , Obesity/geneticsABSTRACT
BACKGROUND: The main symptoms of congenital chloride diarrhea (CCD) main symptoms are watery diarrhea, hypochloremia, and hypokalemic metabolic alkalosis. Silver-Russell syndrome (SRS) is a heterogeneous imprinting disorder characterized by severe intrauterine retardation, poor postnatal growth, and facial dysmorphism. METHODS: Parent-offspring trio whole-exome sequencing was used to identify the causal variants. Sequencing reads were mapped to the reference of human genome version hg19. Sanger sequencing was performed as a confirmatory experiment. RESULTS: The proband was a patient with SRS caused by maternal uniparental disomy 7. The CCD of the proband was caused by homozygous variant c.1515-1 (IVS13) G>A; both mutated alleles were inherited from her mother. CONCLUSION: We report the first clinical case of CCD and SRS occurring together. Patients with milder phenotypes may be difficult to diagnose in early stage, but close monitoring of potential complications is important for identification.
Subject(s)
Chromosomes, Human, Pair 7/genetics , Diarrhea/congenital , Metabolism, Inborn Errors/genetics , Silver-Russell Syndrome/genetics , Uniparental Disomy/genetics , Base Sequence , Chloride-Bicarbonate Antiporters/genetics , Diarrhea/diagnosis , Diarrhea/genetics , Female , Humans , Infant, Newborn , Male , Metabolism, Inborn Errors/diagnosis , Pedigree , Silver-Russell Syndrome/diagnosis , Sulfate Transporters/geneticsABSTRACT
BACKGROUND: Congenital chloride diarrhoea [CLD] is a rare autosomal recessive disease caused by mutations in the solute family carrier 26 member 3 [SLC26A3] gene. Patients suffer from life-long watery diarrhoea and chloride loss. Inflammatory bowel disease [IBD] has been reported in individual patients with CLD and in scl26a3-deficient mice. METHODS: We performed an international multicentre analysis to build a CLD cohort and to identify cases with IBD. We assessed clinical and genetic characteristics of subjects and studied the cumulative incidence of CLD-associated IBD. RESULTS: In a cohort of 72 patients with CLD caused by 17 different SLC26A3 mutations, we identified 12 patients [17%] diagnosed with IBD. Nine patients had Crohn's disease, two ulcerative colitis and one IBD-unclassified [IBD-U]. The prevalence of IBD in our cohort of CLD was higher than the highest prevalence of IBD in Europe [p < 0.0001]. The age of onset was variable [13.5 years, interquartile range: 8.5-23.5 years]. Patients with CLD and IBD had lower z-score for height than those without IBD. Four of 12 patients had required surgery [ileostomy formation n = 2, ileocaecal resection due to ileocaecal valve stenosis n = 1 and colectomy due to stage II transverse colon cancer n = 1]. At last follow-up, 5/12 were on biologics [adalimumab, infliximab or vedolizumab], 5/12 on immunosuppressants [azathioprine or mercaptopurine], one on 5-ASA and one off-treatment. CONCLUSIONS: A substantial proportion of patients with CLD develop IBD. This suggests the potential involvement of SL26A3-mediated anion transport in IBD pathogenesis. Patients with CLD-associated IBD may require surgery for treatment failure or colon cancer.
