Congenital chloride diarrhea
Encyclopedia
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. 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 effect
s, most notably in Finland
.
, it leads to polyhydramnios
and premature birth
. Immediately after birth, it leads to dehydration
, hypoelectrolytemia, hyperbilirubinemia, abdominal distention, and failure to thrive
.
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
.
has been shown to be effective in children.
A potential treatment is butyrate
.
, 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. Two of these diseases, diastrophic dysplasia and congenital chloride diarrhea, are Finnish heritage disease
s.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
due to an autosomal recessive mutation
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
on chromosome 7. The mutation is in downregulated-in-adenoma
Downregulated-in-adenoma
The downregulated-in-adenoma is a membrane protein in intestinal cells. It is an anion exchanger and a member of the sulfate anion transporter family. It mediates chloride and bicarbonate exchange and additionally transports sulfate and other anions at the apical membrane, part of the plasma...
(DRA), a gene that encodes a membrane protein
Membrane protein
A membrane protein is a protein molecule that is attached to, or associated with the membrane of a cell or an organelle. More than half of all proteins interact with membranes.-Function:...
of intestinal cells
Enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...
. The protein belongs to the solute carrier 26 family
Solute carrier family
The solute carrier group of membrane transport proteins include over 300 members organized into 51 families. The SLC gene nomenclature system was originally proposed by the Human Genome Organization and is the basis for the official HUGO names of the genes that encode these transporters...
of membrane transport proteins. More than 20 mutations in the gene are known to date. A rare disease
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
, CCD occurs in all parts of the world but is more common in some populations with genetic founder effect
Founder effect
In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, using existing theoretical work by those such as Sewall...
s, most notably in Finland
Finland
Finland , officially the Republic of Finland, is a Nordic country situated in the Fennoscandian region of Northern Europe. It is bordered by Sweden in the west, Norway in the north and Russia in the east, while Estonia lies to its south across the Gulf of Finland.Around 5.4 million people reside...
.
Pathophysiology
CCD causes persistent secretory diarrhea. In a fetusFetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
, it leads to polyhydramnios
Polyhydramnios
Polyhydramnios is a medical condition describing an excess of amniotic fluid in the amniotic sac. It is seen in 0.2 to 1.6% of pregnancies,,...
and premature birth
Premature birth
In humans preterm birth refers to the birth of a baby of less than 37 weeks gestational age. The cause for preterm birth is in many situations elusive and unknown; many factors appear to be associated with the development of preterm birth, making the reduction of preterm birth a challenging...
. Immediately after birth, it leads to dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
, hypoelectrolytemia, hyperbilirubinemia, abdominal distention, and failure to thrive
Failure to thrive
Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....
.
Diagnosis
CCD may be detectable on prenatal ultrasound. 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.An important feature in this diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
that helps in the diagnosis, is that its the only type of diarrhea that causes metabolic alkalosis
Metabolic alkalosis
Metabolic alkalosis is a metabolic condition in which the pH of tissue is elevated beyond the normal range . This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations.-Terminology:*Alkalosis...
rather than metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
.
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 KClKCL
KCL or KCl may stand for:*KCl, the chemical symbol for potassium chloride*Kirchhoff's current law*King's College London, constituent college of the University of London*Kyoto Common Lisp...
has been shown to be effective in children.
A potential treatment is butyrate
Butyrate
Butyrate is the traditional name for the conjugate base of butanoic acid . The formula of the butanoate ion is C4H7O2-. The archaic name is used as part of the name of butyrates or butanoates, or esters and salts of butyric acid, a short chain fatty acid...
.
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 dysplasiaDiastrophic dysplasia
Diastrophic dysplasia is an autosomal recessive dysplasia which affects cartilage and bone development....
, congenital chloride diarrhea, and Pendred syndrome
Pendred syndrome
Pendred syndrome or Pendred disease is a genetic disorder leading to congenital bilateral sensorineural hearing loss and goitre with occasional hypothyroidism . There is no specific treatment, other than supportive measures for the hearing loss and thyroid hormone supplementation in case of...
are caused by the highly related genes SLC26A2
SLC26A2
The SLC26A2 protein is a member of the solute carrier family. In humans, this transporter is encoded by the SLC26A2 gene.- Function :The diastrophic dysplasia sulfate transporter is a transmembrane glycoprotein implicated in the pathogenesis of several human chondrodysplasias...
(first called DTDST), SLC26A3
SLC26A3
Solute carrier family 26, member 3, also known as SLC26A3, or DRA is a human gene.-Further reading:...
(first called CLD or DRA), and SLC26A4 (first called PDS), respectively. Two of these diseases, diastrophic dysplasia and congenital chloride diarrhea, are Finnish heritage disease
Finnish heritage disease
A Finnish heritage disease is a genetic disease or disorder that is part of the Finnish disease heritage. Finnish heritage diseases are significantly more common in people whose ancestors were ethnic Finns, natives of Finland and Sweden. About 40 rare diseases are regarded as Finnish heritage...
s.