Congenital chloride diarrhea

Congenital chloride diarrhea (CLD, also congenital chloridorrhea) is a genetic disorder due to an autosomal recessive mutation on chromosome 7. The mutation is in downregulated-in-adenoma (DRA), a gene that encodes a membrane protein of intestinal cells. The protein belongs to the solute carrier 26 family of membrane transport proteins.[1] More than 20 mutations in the gene are known to date. A rare disease, CCD occurs in all parts of the world but is more common in some populations with genetic founder effects,[2] most notably in Finland.

Contents

Pathophysiology

CCD causes persistent secretory diarrhea. In a fetus, it leads to polyhydramnios and premature birth. Immediately after birth, it leads to dehydration, hypoelectrolytemia, hyperbilirubinemia, abdominal distention, and failure to thrive.[3]

Diagnosis

CCD may be detectable on prenatal ultrasound.[4][5] After birth, signs in affected babies typically are abdominal distension, visible peristalsis, and watery stools persistent from birth that show chloride loss of more than 90 mmol/l.[5] An important feature in this diarrhea that helps in the diagnosis, is that its the only type of diarrhea that causes metabolic alkalosis rather than metabolic acidosis.

Treatment

Available treatments address the symptoms of CCD, not the underlying defect. Early diagnosis and aggressive salt replacement therapy result in normal growth and development, and generally good outcomes. Replacement of NaCl and KCl has been shown to be effective in children.[6]

A potential treatment is butyrate.[7]

History

Observations leading to the characterization of the SLC26 family were based on research on rare human diseases. Three rare recessive diseases in humans have been shown to be caused by genes of this family. Diastrophic dysplasia, congenital chloride diarrhea, and Pendred syndrome are caused by the highly related genes SLC26A2 (first called DTDST), SLC26A3 (first called CLD or DRA), and SLC26A4 (first called PDS), respectively.[8] Two of these diseases, diastrophic dysplasia and congenital chloride diarrhea, are Finnish heritage diseases.

References

  1. ^ Dorwart MR, Shcheynikov N, Yang D, Muallem S (April 2008). "The solute carrier 26 family of proteins in epithelial ion transport". Physiology (Bethesda, Md.) 23: 104–14. doi:10.1152/physiol.00037.2007. PMID 18400693. 
  2. ^ Kere J, Lohi H, Höglund P (January 1999). "Genetic Disorders of Membrane Transport III. Congenital chloride diarrhea". The American Journal of Physiology 276 (1 Pt 1): G7–G13. PMID 9886972. 
  3. ^ Mäkelä S, Kere J, Holmberg C, Höglund P (December 2002). "SLC26A3 mutations in congenital chloride diarrhea". Human Mutation 20 (6): 425–38. doi:10.1002/humu.10139. PMID 12442266. 
  4. ^ Rose NC, Kaplan P, Scott S, Kousoulis A, Librizzi R (1992). "Prenatal presentation of congenital chloride diarrhea: clinical report and review of the literature". American Journal of Perinatology 9 (5-6): 398–400. doi:10.1055/s-2007-999274. PMID 1418143. 
  5. ^ a b Abdullah AM, Shaheed MM, Katugampola SM, Patel PJ (March 1990). "Congenital chloride diarrhoea: case report and review of the literature". Annals of Tropical Paediatrics 10 (1): 71–4. PMID 1694648. 
  6. ^ Hihnala S, Höglund P, Lammi L, Kokkonen J, Ormälä T, Holmberg C (April 2006). "Long-term clinical outcome in patients with congenital chloride diarrhea". Journal of Pediatric Gastroenterology and Nutrition 42 (4): 369–75. doi:10.1097/01.mpg.0000214161.37574.9a. PMID 16641574. 
  7. ^ Canani RB, Terrin G, Cirillo P, Castaldo G, Salvatore F, Cardillo G, Coruzzo A, Troncone R (August 2004). "Butyrate as an effective treatment of congenital chloride diarrhea". Gastroenterology 127 (2): 630–4. doi:10.1053/j.gastro.2004.03.071. PMID 15300594. 
  8. ^ Kere J (2006). "Overview of the SLC26 family and associated diseases". Novartis Foundation Symposium 273: 2–11; discussion 11–8, 261–4. doi:10.1002/0470029579.ch2. PMID 17120758.