Long‐Term Clinical Outcome in Patients With Congenital Chloride Diarrhea

Hihnala, Satu; Höglund, Pia; Lammi, Laura; Kokkonen, Jorma; Örmälä, Timo; Holmberg, Christer

doi:10.1097/01.mpg.0000214161.37574.9a

Cited by 95 publications

(128 citation statements)

References 34 publications

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“…Mutations found in the SLC26A3 gene have been linked to congenital chloride-losing diarrhea (CLD) (4), a disease in which patients suffer from watery diarrhea containing elevated Cl Ϫ concentrations that can prove fatal if left untreated (52). Clinical management of the disease includes increased dietary uptake of water, KCl, and NaCl (52,53). A recent report also suggests butyrate is effective in controlling the diarrhea (54).…”

Section: Imentioning

confidence: 99%

Congenital Chloride-losing Diarrhea Causing Mutations in the STAS Domain Result in Misfolding and Mistrafficking of SLC26A3

Dorwart

Shcheynikov

Baker

et al. 2008

Journal of Biological Chemistry

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Congenital chloride-losing diarrhea (CLD) is a genetic disorder causing watery stool and dehydration. Mutations in SLC26A3 (solute carrier 26 family member 3), which functions as a coupled Cl ؊ /HCO 3 ؊ exchanger, cause CLD. SLC26A3 is a membrane protein predicted to contain 12 transmembranespanning ␣-helices and a C-terminal STAS (sulfate transporters and anti-sigma-factor) domain homologous to the bacterial anti-sigma-factor antagonists. The STAS domain is required for SLC26A3 Cl ؊ /HCO 3 ؊ exchange function and for the activation of cystic fibrosis transmembrane conductance regulator by SLC26A3. Here we investigate the molecular mechanism(s) by which four CLD-causing mutations (⌬Y526/7, I544N, I675/ 6ins, and G702Tins) in the STAS domain lead to disease. In a heterologous mammalian expression system biochemical, immunohistochemical, and ion transport experiments suggest that the four CLD mutations cause SLC26A3 transporter misfolding and/or mistrafficking. Expression studies with the isolated STAS domain suggest that the I675/6ins and G702Tins mutations disrupt the STAS domain directly, whereas limited proteolysis experiments suggest that the ⌬Y526/7 and I544N mutations affect a later step in the folding and/or trafficking pathway. The data suggest that these CLD-causing mutations cause disease by at least two distinct molecular mechanisms, both ultimately leading to loss of functional protein at the plasma membrane.

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Section: Imentioning

confidence: 99%

Congenital Chloride-losing Diarrhea Causing Mutations in the STAS Domain Result in Misfolding and Mistrafficking of SLC26A3

Dorwart

Shcheynikov

Baker

et al. 2008

Journal of Biological Chemistry

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“…Rozpoznanie choroby opiera się na stwierdzeniu typowych objawów klinicznych, nadmiernego wydalaniu chlorków w kale (>90 mmol/l) oraz utrzymujących się, mimo leczenia, zaburzeń stężenia Na, K, Cl i zasadowicy metabolicznej. Potwierdzeniem rozpoznania, ale niekoniecznie bezwzględnym, jest badanie genetyczne [7][8][9].…”

Section: Omówienieunclassified

“…Nieleczone zaburzenia jonowe w krótkim czasie prowadzą do charakterystycznych dla tej jednostki zaburzeń gazometrycznych i elektrolitowych, takich jak: alkaloza metaboliczna, hiponatremia, hipokaliemia oraz hipochloremia. Choroba ta rzadko jest rozpoznawana w okresie noworodkowym i wczesnoniemowlęcym [7][8][9]. W pracy prezentujemy chłopca, u którego rozpoznanie biegunki chlorowej zostało postawione w 1,5 miesiącu życia.…”

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Diagnostic difficulties of electrolyte and acid-base disorders present in 1.5 month old boy – a case study

Kik¹,

Noczyńska²

2014

Pediatr. Endocrinol.

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STRESZCZENIE/ABSTRACTPraca dotyczy 1,5-miesięcznego chłopca przyjętego do Kliniki z powodu hiponatremii oraz odwodnienia z podejrzeniem wrodzonego przerostu nadnerczy. W badaniach laboratoryjnych stwierdzono: hiponatremię, hipokaliemię, hipochloremię oraz zasadowicę metaboliczną. U dziecka wykluczono wrodzony przerost nadnerczy jako przyczynę zaburzeń gospodarki kwasowo-zasadowej i wodno-elektrolitowej. Analizując dane z wywiadu (zapalenie płuc, niedrożność smółkowa, dyselektrolitemia, słaby przyrost masy ciała), wykonano diagnostykę w kierunku mukowiscydozy, którą w oparciu o badanie jontoforezy pilokarpinowej oraz badanie genetyczne również wykluczono. Na podstawie badań laboratoryjnych (poziom chlorków w surowicy i kale, obraz kliniczny) ustalono, że przyczyną obserwowanych zaburzeń jest wrodzona biegunka chlorowa, której wiodącym objawem były utrata łaknienia, słaby przyrost masy ciała, niepokój i okresowe wymioty. Endokrynol. Ped. 13/2014;2(47):85-88.The subject of the study is a 1.5 month old baby boy admitted to the clinic with hyponatremia and dehydration with suspected congenital adrenal hyperplasia. Laboratory findings showed hyponatremia, hypochloremia, hypokalemia, metabolic alkalosis. Congenital adrenal hyperplasia was excluded as a cause of acid-base homeostasis disorder, water-electrolyte imbalance. Upon analysis of medical history (pneumonia, dysmolity, electrolyte balance disorder, slow weight increase) pilocarpine iontophoresis as well as genetic testing for mucoviscidosis were performed but mucoviscidosis was also excluded. On the basis of laboratory findings (chloride concentration level in serum and fecal secretion of chloride and clinical findings) it was determined that the symptoms were caused by congenital chloride diarrhea. The prevailing symptoms of the disease were: lack of appetite, slow weight gain, anxiety and periodical vomiting.

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“…The sweat chloride level was normal and cystic fibrosis mutational analysis was negative in our patient. We should be aware that increased concentrations of sweat Cl -were reported in 12% of CLD patients (7). Other causes of pseudo-Bartter syndrome, such as chronic diuretic usage, chronic administration of a chloride-deficient diet, bulimia, cyclic vomiting, and abuse of laxatives, were absent in our patient (14). )…”

Section: Case Reportmentioning

confidence: 99%

A Turkish case of congenital chloride diarrhea with SLC26A3 gene (c.2025_2026insATC) mutation: Diagnostic pitfalls

Hoşnut

Öncel²,

Öncel³

et al. 2010

Turk J Gastroenterol

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Long‐Term Clinical Outcome in Patients With Congenital Chloride Diarrhea

Abstract: When early diagnosed and adequately treated, the long-term prognosis of CLD is favorable. A putative role of a primary anion exchange defect of SLC26A3 in male subfertility and the decline of renal function due to chronic dehydration deserve further characterization.

Cited by 95 publications

References 34 publications

Congenital Chloride-losing Diarrhea Causing Mutations in the STAS Domain Result in Misfolding and Mistrafficking of SLC26A3

Congenital Chloride-losing Diarrhea Causing Mutations in the STAS Domain Result in Misfolding and Mistrafficking of SLC26A3

Diagnostic difficulties of electrolyte and acid-base disorders present in 1.5 month old boy – a case study

A Turkish case of congenital chloride diarrhea with SLC26A3 gene (c.2025_2026insATC) mutation: Diagnostic pitfalls

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