Congenital Diarrheal Disorders: Improved Understanding of Gene Defects Is Leading to Advances in Intestinal Physiology and Clinical Management

Abstract

Congenital diarrheal disorders (CDD, Online Mendelian Inheritance in Man [OMIM] 251850) represent one of the most challenging clinical conditions for pediatric gastroenterologists because of the severity of the clinical picture and the broad range of disorders in its differential diagnosis. The number of conditions included within CDD has gradually increased. Recent advances made in the pathophysiology of these conditions have led to a better understanding of the more common diarrheal diseases. Based on the body of data accumulated in recent years, we suggest that CDD be classified in 4 categories depending on the alteration in absorption and transport of nutrients and electrolytes, enterocyte differentiation and polarization, enteroendocrine cell differentiation, and modulation of the intestinal immune response. Our knowledge of the genes responsible for CDD is also rapidly increasing, thanks to linkage studies based on genome-wide analysis of polymorphisms. In this context, the identification of disease genes is a step forward in the diagnostic approach to a patient in whom CDD is strongly suspected. However, it is conceivable that faster, less expensive molecular procedures will, in the near future, become available. This approach could spare the patient invasive procedures and limit complications associated with a delay in diagnosis. Furthermore, carrier and prenatal molecular diagnosis may help pediatricians better manage the condition in the early stages of life.

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

“…DGAT1 mutations have been identified by exome sequencing in two families, and found to be associated with severe diarrhea resembling a group of congenital diarrheal disorders [70]. In the initial family identified, two siblings carried homozygous DGAT1 loss-of-function mutations and developed intractable diarrhea within 3 days of birth [71].…”

The epigenetic effects of butyrate: potential therapeutic implications for clinical practice

“…Histone deacetylase inhibitors reduce the oxidative damage in X-ALD cells, moreover they could induce the expression of the closest homolog of ABCD1, the redundant gene ABCD2, which should be able to compensate for the lack of functional ABCD1 in X-ALD patients [36]. Congenital chloride diarrhea (CLD) is another inherited disorder in which butyrate therapy has been shown to be beneficial [37,38]. CLD is a rare genetic disease caused by mutations in the gene encoding the solute-linked carrier family 26-member A3 (SLC26A3) protein, which acts as a plasma membrane anion exchanger for Cl - and HCO 3 - .…”

Congenital Diarrheal Disorders: An Updated Diagnostic Approach

“…Congenital diarrheal disorders (CDDs) are a group of inherited enteropathies with a typical onset early in the life [1–3]. Most CDDs display similar clinical presentation despite different outcomes.…”

“…Milder forms of CDDs, with less severe clinical picture that remain undiagnosed until later ages, have been described. The less severe outcome may depend on a milder effect of mutations in the disease gene [1–3]. In most cases of CDDs the disease-gene is known [4].…”