CODE Disorders

Overview

Congenital Diarrheas and Enteropathies (CODEs) are a group of genetic diseases, causing diarrhea that usually present early in life. They are primarily characterized by structural or functional abnormalities in the cells that line the intestine (epithelial cells). There at least 25 different known genes that are associated with CODE disorders. For more information about specific CODE disorders please click on the menu to the left.

Infants with CODEs often depend on specialized nutrition support and each CODE disorder has unique clinical characteristics and outcomes that depend on the type of CoDE disorder

CODE disorders can be classified into different categories -please see the Evaluation of CODE disorders for more information.

Microvillus Inclusion Disease

What is microvillus inclusion disease?

Microvillus inclusion disease (MVID) is a rare genetic disease of the intestine that causes severe diarrhea and an inability to absorb nutrients. It usually starts soon after birth and is one of a group of disorders termed congenital diarrheas.

In MVID, the surface of the cells that line the intestine does not develop normally. This causes these cells not to work properly to absorb fluid and nutrients coming into the intestine.

Several genes have been identified that are thought to be involved in MVID. Infants and children with this disease usually need specialized intravenous nutrition (parenteral nutrition) in order to grow normally and avoid dehydration.

What are the symptoms of microvillus inclusion disease?

Signs of MVID usually show up within hours or days after birth. However, sometimes the symptoms show up later (around two months after birth) and are less severe.

Generally, babies have severe, watery diarrhea that doesn’t go away and cannot absorb the nutrients that they eat. This can lead to other severe complications, such as life-threatening

dehydration, requiring the infant to be hospitalized. There may also be related poor weight gain.

What causes microvillus inclusion disease?

MVID is inherited as an autosomal recessive genetic trait. This means that both parents must carry a copy of the affected gene in order to pass the disease on to their child. In some families, more than one child is affected. The genes that have been identified include Myosin 5b and Syntaxin 3.

How is microvillus inclusion disease diagnosed?

Diagnosing microvillus inclusion disease (MVID) involves a number of steps. First doctors will test to determine the kind of diarrhea involved and which nutrients cannot be absorbed.

If they suspect a congenital diarrhea, they will need to look at a sample of the tissue in the small intestine. To do this they will need to perform a procedure called an endoscopy, which uses a small flexible viewing tube to look at the intestine and obtain tiny tissue samples (biopsies).

Once they have a sample they will look at it under a microscope as well as with a special microscope (electron microscope). Using electron microscopy, doctors can detect the main features of microvillus inclusion disease, which are tiny but distinct differences in the cells of the small

intestine.

In addition to these tests, doctors will perform genetic testing to see whether there are any differences in the genes known to cause MVID and other congenital diarrheas.

How is microvillus inclusion disease treated?

There are currently no drug treatments for MVID. Treatment is supportive and involves long-term maintenance of nutrition and hydration with parenteral nutrition.

Research in Microvillus Inclusion Disease

The PediCODE consortium has several research projects involving Microvillus Inclusion Disease.

These include studies to better understand the cell biology of the disease as well as looking for new treatments or approaches to management. For more information on these studies please see here Studies page contact the nearest consortium center site consortium contact page, or Patient Resources

Congenital Chloride Diarrhea (CCD)

What is Congenital Chloride Diarrhea?

CCD is a rare genetic disease that causes diarrhea, and dehydration.

The protein that is responsible for CCD is named SLC26A3 which is a protein that is required for the absorption of chloride by the intestine. If the SLC26A3 protein malfunctions or is absent, an individual will show symptoms associated with CCD.

Depending on the disease severity, CCD will alter a child’s ability to absorb chloride resulting in diarrhea.

What are the symptoms of Congenital Chloride Diarrhea?

An individual child present initially with intestinal symptoms, dehydration and growth failure in varying degrees of severity.

Neonates with CCD have watery diarrhea with stools enriched with chloride and continues even when the child is fasting. Pregnancy may be complicated by premature delivery and polyhydramnios (excessive amniotic fluid).

The diarrheal symptoms continue throughout life and can be worse with any unrelated fever or infection (upper respiratory tract infection), and these exacerbations may require hospitalization.

What causes Congenital Chloride Diarrhea?

CCD is classified as a monogenic disorder because the disease is caused by the dysfunction of a single gene. For a child to have CCD and its associated symptoms, they must inherit two dysfunctional SLC26A3 genes, one from each parent.

How is Congenital Chloride Diarrhea diagnosed?

CCD can be anticipated when mothers have an excessive amount of amniotic fluid that occasionally requires medical therapy and even drainage of the fluid.

A child with CCD presents with diarrheal symptoms shortly after birth, and it does not improve during fasting. The diarrhea may be so severe and liquidity that it may be confused for urine.

Testing of stool samples for electrolytes show an unusually elevated chloride level, and blood samples has an excessive amount of base.

The diagnosis of CCD can generally be established with dietary trials, but on occasions, doctors will perform an endoscopy by using a small flexible tube to look at the intestines. During the endoscopy, tiny tissue samples (biopsies) are collected for microscopic analysis. A normal appearing tissue sample is a sign of CCD. If CCD is suspected, definitive diagnosis occurs through genetic testing using blood samples.

How is Congenital Chloride Diarrhea treated?

There is no curative treatment for CCD at the present. Current disease management limited to the oral intake of salt (sodium and chloride) and potassium in order to replace what is lost in the stools. Other drugs such as certain types of antacids (proton-pump inhibitors).

Research in Congenital Chloride Diarrhea.

Several international research institutes are conducting research to uncover the role of SLC26A3 in electrolyte absorption in the gastrointestinal system. For more information on CCD please click here to obtain an in-depth review of SLC26A3’s biology, genetics, clinical features, therapies, and outcomes.

DGAT-1 Deficiency

What is DGAT-1 deficiency?

DGAT-1 deficiency is a rare genetic disease that one is born with, and if untreated, causes diarrhea from close to birth, poor nutrient absorption, leaking and loss of protein from the body through the bowel wall and poor growth.
 
DGAT-1 (diacylglycerol-acyltransferase 1) helps in the production of certain fats in the intestine that are called triglycerides (TG), the main energy fuel stored in human fat tissue. If the DGAT-1 protein malfunctions or is absent, an individual will show symptoms associated with DGAT-1 deficiency.
 
Left untreated, DGAT-1 deficiency can alter a child’s nutritional status, quality of life, development, and life expectancy.
 

What are the symptoms of DGAT-1 deficiency?

A child with DGAT-1 deficiency will present t birth or in the first few weeks of life with diarrhea, poor absorption of fats, low levels in the body of some important vitamins that depend on fat absorption such as Vitamin D, leaking of proteins from the gut, and ultimately then leading to poor nutrition and poor growth. Some may have recurrent infections.
 

What causes DGAT-1 deficiency?

DGAT-1 -deficiency is classified as a monogenic disorder because the disease is caused by the dysfunction of a single gene. For a child to have DGAT1-deficiency and its associated symptoms, they must inherit two dysfunctional DGAT-1 genes, one from each parent. The parents themselves typically have no symptoms since they are carrying only one defective gene.
 

How is DGAT-1 deficiency diagnosed?

If a child presents with the intestinal symptoms described above that are prolonged and difficult to manage, doctors will often perform an endoscopy by using a small flexible tube to look at the intestines.
 
During the endoscopy, tiny tissue samples (biopsies) are collected for analysis under a microscope.
 
Viewed under the microscope, the tissue is stained with special stains or dyes that might suggest the diagnosis of DGAT1. If DGAT1-deficiency is suspected from the clinical history and/or the biopsies, the diagnosis of DGAT-1 is confirmed through genetic testing using samples from the blood or from the saliva of the child, and often from samples from the parents as well.
 

How is DGAT1-deficiency treated?

Initially, while the diagnosis is still unknown or still being investigated, nutrition delivered through the veins is often needed to supplement what is delivered to the gut or taken by mouth. Once the diagnosis is confirmed or strongly suspected, a very low fat or minimal fat diet often leads to resolution or improvement in symptoms, as well as improvement in growth. Since this therapy of following a very low fat diet is relatively new, long term outcomes are still not clear, but appear quite promising.
 

Research in DGAT1-deficiency

Several research groups are conducting research to uncover how DGAT1 causes intestinal damage and leakiness, and to understand how it may be better treated. For more information on research published by the PediCODE consortium on DGAT1 deficiency and its improvement with a very low fat diet, please click here.

TTC7A-Deficiency

What is TTC7A-deficiency?

TTC7A-deficiency is a rare genetic disease that causes diarrhea, inflammation of the intestines, bowel obstructions, poor nutrient absorption, and a weakened immune system.

Tetratricopeptide repeat domain 7A (TTC7A) is a protein that helps to maintain healthy intestinal and immune function. If the TTC7A protein malfunctions or is absent, an individual will show symptoms associated with TTC7A-deficiency.
 
Depending on the disease severity, TTC7A-deficiency can alter a child’s quality of life, development, and life expectancy.
 

What are the symptoms of TTC7A-deficiency?

An individual child may present with one or more intestinal and immune symptoms in varying degrees of severity. TTC7A-deficiency symptoms are typically grouped into 3 distinct clinical conditions: inflammatory bowel disease (IBD), multiple intestinal atresia (MIA) and combined immunodeficiency (CID).
 
50% of children with TTC7A-deficiency have IBD, which can produce bloody and watery diarrhea, abdominal pain and problems with nutritional absorption leading to growth delay. If IBD affects children under the age of 6, it is termed very early onset inflammatory bowel disease (VEOIBD).
 
MIA is associated with serious and reoccurring bowel obstructions that often require surgery. The blockages can be numerous and located anywhere along the small and large intestine.
 
Over 50% of children with IBD and/or MIA show signs of CID. CID is related to low numbers of white blood cells and reduced antibodies leading to an increased number of infections.
 
Children with TTC7A-deficiency may also have conditions affecting the hair, skin, teeth, nails, and liver function.
 

What causes TTC7A-deficiency?

TTC7A-deficiency is classified as a monogenic disorder because the disease is caused by the dysfunction of a single gene. For a child to have TTC7A-deficiency and its associated symptoms, they must inherit two dysfunctional TTC7A genes, one from each parent.
 

How is TTC7A-deficiency diagnosed?

If a child presents with intestinal symptoms that are difficult to manage, doctors will perform an endoscopy by using a small flexible tube to look at the intestines. During the endoscopy, tiny tissue samples (biopsies) are collected for microscopic analysis. Increases in the number of dead cells in the patient’s tissue sample is a sign of TTC7A-deficiency. If TTC7A-deficiency is suspected, definitive diagnosis occurs through genetic testing using blood samples.
 

How is TTC7A-deficiency treated?

There is no curative treatment for TTC7A-deficiency at the present. Current disease management focuses on symptom control. Immune dysfunction can be improved by bone marrow transplant and intestinal obstructions can be surgically removed. IBD is treated with medications such as immunosuppressives, steroids, and antibody therapy (biologics). Most patients experience a poor quality of life as these
treatments do not reverse the disease and are associated with adverse side effects.
A recent drug study has provided preliminary evidence that Leflunomide, a drug already approved for use in juvenile rheumatoid arthritis, may be effective in improving the intestinal disease in TTC7A-deficiency. Patient testing with Leflunomide has been limited thus far, however, early results suggest a positive response in some patients.
 

Research in TTC7A-deficiency.

Several international research institutes are conducting research to uncover the role of TTC7A in the immune and gastrointestinal system. For more information on TTC7A please click here to obtain an in depth review of TTC7A’s biology, genetics, clinical features, therapies, and outcomes.

Tufting Enteropathy

What is Tufting enteropathy?

Tufting enteropathy is a rare genetic disease of the intestine that causes severe diarrhea and an inability to absorb nutrients. The condition usually starts soon after birth and is one of a group of disorders termed congenital diarrheas.

Tufting enteropathy occurs when the surface cells lining the intestine do not develop normally — causing an inability to absorb fluid and nutrients entering the intestine. Infants and children with this disease usually need specialized intravenous nutrition (parenteral nutrition) in order to grow normally and avoid dehydration.

What are the symptoms and causes of Tufting enteropathy?

Signs of tufting enteropathy usually present within hours or days after birth. However, sometimes the symptoms appear later (around two months after birth) and are less severe.

When babies have severe, watery diarrhea that doesn’t go away, they cannot absorb the nutrients that they eat. This can lead to other severe complications, such as life-threatening dehydration, requiring them to be hospitalized. They also may have difficulty gaining weight.
 
Tufting enteropathy is inherited as an autosomal recessive genetic trait. This means that both parents must carry a copy of the affected gene in order to pass the disease on to their child. In some families, more than one child is affected. The gene so far identified is called EpCAM.

How is Tufting enteropathy diagnosed?

Testing for tufting enteropathy involves a number of steps. First doctors will test to determine the kind of diarrhea involved and which nutrients cannot be absorbed. If they suspect a congenital diarrhea they will need to look at a sample of the tissue in the small intestine. To do this they will need to perform a procedure called an endoscopy, which uses a small flexible viewing tube to look at the intestine and obtain tiny tissue samples (biopsies). Once they have a sample they will look at it under a light microscope as well as with a special microscope (electron microscope). Using microscopy, doctors can detect the main features of tufting enteropathy, which are tiny but distinct differences in the cells of the small intestine.

In addition to these tests, doctors will perform genetic testing to see whether there are any differences in the genes known to cause tufting enteropathy and other congenital diarrheas.

How is Tufting enteropathy treated?

There are currently no drug treatments for tufting enteropathy. Treatment is supportive and involves long-term maintenance of nutrition and hydration with chronic parenteral nutrition.

Research in Tufting enteropathy

The PediCODE consortium is working to understand the natural history of tufting enteropathy and to improve management of the disease. We are also working to develop new resources to allow researchers to study the underlying biology in order to develop new therapies. For more information on our studies please see here or contact the nearest consortium center site, or see our Patient Resources.

Glucose Galactose Malabsorption (GGM)

What is GGM?

GGM is a rare genetic disease that causes diarrhea, and dehydration.

The protein that is responsible for GGM is named SLC5A1 which is a protein that is required for the absorption of dietary glucose by the intestine. If the SLC5A1 protein malfunctions or is absent, an individual will show symptoms associated with GGM.

Depending on the disease severity, GGM will alter a child’s ability to absorb glucose containing carbohydrates.

What are the symptoms of GGM?

An individual child present initially with intestinal symptoms, dehydration and growth failure in varying degrees of severity.

Neonates with GGM have watery diarrhea that is made worse with the majority of standard formulas.

What causes GGM?

GGM is classified as a monogenic disorder because the disease is caused by the dysfunction of a single gene. For a child to have GGM and its associated symptoms, they must inherit two dysfunctional SLC5A1 genes, one from each parent.  

How is GGM diagnosed?

If a child presents with diarrheal symptoms shortly after birth, doctors can perform dietary trials to first understand whether formulas with certain nutrients are associated with worsening diarrhea. A child with GGM can tolerate any formula or foods that do not contain any glucose, or galactose, two simple sugars (monosaccharides). In GGM, the intolerance to glucose and galactose includes when they are in more complex carbohydrates such as lactose, starch and table sugar.

The diagnosis of GGM can generally be established with dietary trials, but on occasions, doctors will perform an endoscopy by using a small flexible tube to look at the intestines. During the endoscopy, tiny tissue samples (biopsies) are collected for microscopic analysis. A normal appearing tissue sample is a sign of GGM. If GGM is suspected, definitive diagnosis occurs through genetic testing using blood samples.

How is GGM treated?

There is no curative treatment for GGM at the present. Current disease management limited to strict dietary elimination of glucose and galactose containing foods. This strict dietary restriction is life-long, and foods that are enriched with fructose and limited glucose and galactose are tolerable.

Research in GGM.

Several international research institutes are conducting research to uncover the role of SLC5A1 in nutrient absorption in the gastrointestinal system. The PediCODE consortium is working on understanding how gene defects that affect absorption of nutrients lead to malnutrition and how management of these disorders can be improved.

Chylomicron Retention Disease (CMRD; also known as Anderson’s Disease)

What is CMRD?

CMRD is a rare genetic disease that one is born with, and typically presents in infancy with diarrhea, vomiting and poor growth. The stools are often greasy due to poor absorption of fat by the intestine leading to loss of fat in the stool and poor absorption of some key vitamins. Untreated, these vitamin deficiencies can affect other functions of the body such as the function of the nerves in the body.

The genetic mutation in CMRD leads to decreased levels of an enzyme called guanosine triphosphatase (Sar1b GTPase or Sar1b), which is involved in moving fat across the intestinal cell and into the body through chylomicrons, the principal carriers of fats from the diet.  When Sar1b is deficient, this leads to poor transport of fat and chylomicrons across the intestinal cells and into the body, resulting in poor absorption of fat. This often leads to malnutrition as well as low cholesterol levels. Since fat absorption is also necessary for the absorption of some vitamins, then this may lead to poor absorption of some vitamins that typically dissolve well in fat, such as Vitamin E, Vitamin D, Vitamin A and Vitamin K (also called fat-soluble Vitamins).

Left untreated, CMRD deficiency can alter a child’s nutritional status, quality of life, development, and life expectancy.

What are the symptoms of CMRD?

A child with CMRD will typically present with diarrhea in the first few months after birth, along with poor growth. Vomiting and abdominal distention are also often present. Once the diagnosis is made, these symptoms get better within weeks of starting a low-fat diet. Poor fat absorption will continue if regular fat is reintroduced. Vitamin E levels are low and require supplementation chronically and remain low despite supplementation, so very high doses are often needed. This may lead to neurologic symptoms over time. Vitamins D, K, A are often decreased, but can easily be corrected with oral supplementation. Untreated vitamin deficiencies can lead to neurological, muscular and vision complications.

In some patients, the liver maybe enlarged and also have fat trapped in it, but does not typically represent a major issue for patients with CMRD.

What causes CMRD deficiency?

CMRD results form a mutation in the SAR1B gene, the gene that controls the production of the Sar1b enzyme. CMRD is classified as a monogenic disorder because the disease is caused by the dysfunction of a single gene. For a child to have CMRD and its associated symptoms, they must inherit two dysfunctional CMRD genes, one from each parent.   The parents themselves typically have no symptoms since they are carrying only one defective gene.

How is CMRD diagnosed?

If a child presents with the intestinal symptoms described above that are prolonged and difficult to manage, doctors will often perform an endoscopy by using a small flexible tube to look at the intestines. The intestine may have a white appearance due to the fat deposited in the lining During the endoscopy, tiny tissue samples (biopsies) are collected for analysis under a microscope. Viewed under the microscope, the tissue is stained with special stains or dyes that might suggest the diagnosis of CMRD, showing fat trapped in the cells lining the intestine. If CMRRD is suspected from the clinical history and/or the biopsies, the diagnosis of CMRD is confirmed through genetic testing for mutations in the SAR1B gene using samples from the blood or from the saliva of the child, and often from samples from the parents as well.

Note that cholesterol levels in the blood are low, which can often clue the doctors about the possibility of this diagnosis.

How is CMRD treated?

Once the diagnosis is confirmed or strongly suspected, a very low fat or minimal fat diet that allows a special type of fat called medium-chain triglyceride (MCT) often leads to resolution or improvement in symptoms, as well as improvement in growth. In infants, milk preparations with

MCT fat are often used. In older children, a regimen low in long chain

fatty acids is usually sufficient, while making sure that children still receive some key fats the body needs (essential fatty acids). Extra vitamins need to be added to the diet, and sometimes at very high doses in particular for Vitamin E and Vitamin A.

Research in CMRD.

Some research groups are conducting research to uncover how CMRD causes malabsorption, and to understand how it may be better treated. The PediCODE consortium is working on understanding how gene defects that affect absorption of nutrients lead to malnutrition and how they can be improved with treatments such as consuming a very low-fat diet.

Trichohepaticenteric Syndrome

What is Trichohepaticenteric Syndrome?

This syndrome is named after observations of the disease’s “clinical findings” which affect the hair (tricho), liver (hepatic) and intestinal absorption (enteric). It is a genetic condition that is inherited and is caused by mutations in the following genes: TTC37 or SVIV2L.

The syndrome is rare and can be variable in presentation and symptoms requiring specialized care with a hepatologist monitoring liver function and gastroenterologist to help manage nutrition. Most patients will require specialized intravenous nutrition.

What are the symptoms?

Symptoms of Trichohepaticenteric Syndrome can vary in severity, but typically are observed to have the affect the following body systems: hair, liver, intestines, and immune system.

Hair: Children with this condition are described to have brittle/wooly-like hair.

Liver: This can be extremely variable in patients ranging from minor liver disease to cirrhosis (severe liver damage). Children can also have changes to the size (larger) and appearance of the liver.

Intestine: The typical presentation is chronic diarrhea in infancy with variable absorption of nutrients requiring close monitoring and specialized intravenous nutrition.

Other: Children with Trichohepaticenteric syndrome may also present with alterations to their immune system (weak immune system) and changes to the texture (dryness) of their skin.

What causes Trichohepaticenteric Syndrome?

Trichohepaticenteric syndrome is inherited and caused by mutations in one of these two genes: TTC37 or SKIV2L.

Inheritance of a mutation in either of these genes is autosomal recessive which means both parents are carriers of this gene mutation. Of note, being a carrier of this gene mutation does not result in the clinical symptoms or syndrome. To have this syndrome the child has acquired two genes with mutations.

It is still unclear how the mutation of these genes leads to the disease seen in different organ systems and how this translates to the varied clinical symptoms.

How is Trichohepaticenteric Syndrome Diagnosed?

When there is an infant/child that is demonstrating symptoms that are consistent with the trichohepaticenteric syndrome including hair abnormalities, liver disease and chronic infantile-onset diarrhea, this will often lead to further evaluation by a gastroenterologist. Initial evaluation often includes endoscopy (a procedure that allows doctors to see and take samples from the intestines) and looking at intestinal biopsies samples under microscope) and genetic testing.

How is Trichohepaticenteric Syndrome Treated?

There is currently no medical or surgical cure for Trichohepaticenteric syndrome with treatment focused on symptom support and prevention of clinical disease such as progression of liver disease and poor development/growth due to malabsorption.

Most patients require specialized intravenous nutrition called “parenteral nutrition” and this requires close follow-up and monitoring by a gastroenterologist to ensure adequate weight gain, as well as appropriate vitamin and mineral provision. This type of nutrition support can potentially be weaned over time, depending on the extent of malabsorption seen clinically, which can vary.

Depending on the extent of liver disease, children are often followed by a hepatologist for ongoing monitoring of liver health with some patients requiring a liver transplant if their syndrome is associated with a severe form of liver disease.

Other specialized doctors may be needed such as, an immunologist, if the patient has a weakened immune system requiring treatment and close follow-up to prevent infections.

Research in Trichohepaticenteric Syndrome

The PediCODE consortium is working to understand the natural history of Trichohepaticenteric syndrome and to improve management of the disease. We are also working to develop new resources to allow researchers to study the underlying biology in order to develop new therapies. For more information on our studies please see here or contact the nearest consortium center site or see our Patient Resources.

NEUROG3-Deficiency

What is NEUROG3-deficiency or enteric anendocrinosis?

NEUROG3-deficiency is a rare genetic disease that causes diarrhea, poor nutrient absorption, diabetes mellitus, and other problems with the endocrine system.

Neurogenin3 (NEUROG3) is a protein that is required by the intestine and pancreas to generate cells that produce hormones that is required for healthy intestinal and pancreatic function. If the NEUROG3 protein malfunctions or is absent, an individual will show symptoms associated with NEUROG3-deficiency.

Depending on the disease severity, NEUROG3-deficiency can alter a child’s quality of life, development, and life expectancy.

What are the symptoms of NEUROG3-deficiency?

An individual child may present initially with intestinal symptoms in varying degrees of severity. NEUROG3-deficiency symptoms are typically grouped into 2 distinct clinical conditions: intestinal (enteric) and systemic endocrine problems.

Neonates with NEUROG3-deficiency have watery diarrhea that is made worse with any type of formula.

At a later age, children frequently develop symptoms suggestive of diabetes, including excessive thirst and urination.

Children with NEUROG3-deficiency may also have symptoms associated with delayed sexual development.

What causes NEUROG3-deficiency?

NEUROG3-deficiency is classified as a monogenic disorder because the disease is caused by the dysfunction of a single gene. For a child to have NEUROG3-deficiency and its associated symptoms, they must inherit two dysfunctional NEUROG3 genes, one from each parent.

How is NEUROG3-deficiency diagnosed?

If a child presents with intestinal symptoms that are difficult to manage, doctors will perform an endoscopy by using a small flexible tube to look at the intestines. During the endoscopy, tiny tissue samples (biopsies) are collected for microscopic analysis. A decline in the number of hormone-producing cells in the patient’s tissue sample is a sign of NEUROG3-deficiency. If NEUROG3-deficiency is suspected, definitive diagnosis occurs through genetic testing using blood samples.

How is NEUROG3-deficiency treated?

  1. There is no curative treatment for NEUROG3-deficiency at the present. Current disease management focuses on symptom control. Intravenous nutrition for the first several years of life is helpful to minimize the diarrhea and improve growth. Beyond 2 years of age, most children can stop intravenous nutrition and rely on normal formulas and foods. Loperamide can also be used to control the severity of the diarrhea.
  2. The diabetes mellitus symptoms can be managed in the usual manner with a sugar restricted diet and insulin shots.

Research in NEUROG3-deficiency.

Several international research institutes are conducting research to uncover the role of NEUROG3 in the diabetes and gastrointestinal system. The PediCODE consortium is working on understanding how gene defects that affect absorption of nutrients lead to malnutrition and new treatments for these disorders. For more information on these studies please see here contact the nearest consortium center site, or our Patient Resources.

PCSK1-Deficiency

What is PCSK1-deficiency or enteric dysendocrinosis?

PCSK1-deficiency is a rare genetic disease that causes diarrhea, poor nutrient absorption, obesity, and other problems with the endocrine system.

Proprotein Convertase 1/3 (PCSK1) is a protein that is required by the intestine, thyroid gland, pituitary gland and pancreas to generate normal hormones that is required for healthy intestinal and other endocrine function. If the PCSK1protein malfunctions or is absent, an individual will show symptoms associated with PCSK1-deficiency.

Depending on the disease severity and appropriate medical management, PCSK1-deficiency can alter a child’s quality of life, development, and life expectancy.

What are the symptoms of PCSK1-deficiency?

A child may present initially with intestinal symptoms (diarrhea) in varying degrees of severity. PCSK1-deficiency symptoms are typically grouped into 2 distinct clinical conditions: intestinal (enteric) and systemic endocrine problems.

Neonates with PCSK1-deficiency have watery diarrhea that is made worse with any type of formula.

Children frequently develop symptoms suggestive of hypoglycemia (low blood glucose level), including lethargy, excessive sweating, and shakiness.

Children with PCSK1-deficiency may also have symptoms associated with hypothyroidism, including fatigue, and cold intolerance.

PCSK1-deficiency may also result in hypoadrenalism and have symptoms such as fatigue and hypoglycemia.

Growth hormone deficiency occasionally occurs in children with PCSK1-deficiency and this should be suspected in those patients that are have poor linear (height) growth.

Children with PCSK1-deficiency may also have symptoms associated with diabetes insipidus, including excessive thirst and urination, but have an elevated blood salt (sodium) concentration and normal glucose levels.

Children with PCSK1-deficiency may also have symptoms associated with delayed sexual development.

Significant obesity occurs in many children with PCSK1-deficiency and includes excessive desire to eat.

What causes PCSK1-deficiency?

PCSK1-deficiency is classified as a monogenic disorder because the disease is caused by the dysfunction of a single gene. For a child to have PCSK1-deficiency and its associated symptoms, they must inherit two dysfunctional PCSK1 genes, one from each parent.

How is PCSK1-deficiency diagnosed?

Children who are suspected as having PCSK1-deficiency should have an elevated blood pro-insulin level.

Children with intestinal symptoms that are difficult to manage, doctors will perform an endoscopy by using a small flexible tube to look at the intestines. During the endoscopy, tiny tissue samples (biopsies) are collected for microscopic analysis. A normal number of hormone-producing cells in the patient’s tissue sample is a sign of PCSK1-deficiency.

If PCSK1-deficiency is suspected, definitive diagnosis occurs through genetic testing using blood samples.

How is PCSK1-deficiency treated?

  1. There is no curative treatment for PCSK1-deficiency at the present. Current disease management focuses on symptom control. Intravenous nutrition for the first several years of life is helpful to minimize the diarrhea and improve growth. Beyond 2 years of age, most children can stop intravenous nutrition and rely on normal formulas and foods. Loperamide can also be used to control the severity of the diarrhea.
  2. The systemic endocrine problems associated with PCSK1-deficiency, including hypothyroidism, hypoadrenalism, Growth hormone deficiency and diabetes insipidus, can be managed by specific hormonal replacement therapy.

Research in PCSK1-deficiency.

Several international research institutes are conducting research to uncover the role of PCSK1 in the gastrointestinal and systemic endocrine system. For more information on these studies please see here contact the nearest consortium center site, or our Patient Resources.