Microvillous Inclusion Disease

Microvillous inclusion disease is a rare inherited intestinal disorder that causes severe, life-threatening diarrhea in infants, typically beginning within hours or days after birth. The disease affects the cells lining the small intestine, making it impossible for the body to absorb nutrients and fluids from food.

Table of contents

• What is microvillous inclusion disease?
• Disease identification codes
• Other names for this condition
• Associated anatomy
• Symptoms and clinical presentation
• Causes and inheritance
• How the disease is diagnosed
• Treatment and management
• How common is the disease

What is microvillous inclusion disease?

Microvillous inclusion disease (MVID) is a rare genetic disease of the intestine that causes severe diarrhea and an inability to absorb nutrients^[1]. It is characterized by chronic, watery, life-threatening diarrhea typically beginning in the first hours to days of life^[2]. The disease is one of a group of disorders called congenital diarrheas, meaning it is present from birth^[1].

In MVID, the surface of the cells that line the intestine does not develop normally^[1]. These cells, called enterocytes, are normally covered with tiny finger-like structures called microvilli. These microvilli greatly increase the surface area of the cells, allowing them to absorb nutrients and fluids efficiently as food passes through the intestine^[2]. In children with MVID, the microvilli are either absent, malformed, or not fully developed^[11]. This means the absorption step of digestion is essentially skipped, causing severe problems^[20].

A distinctive feature of MVID, visible under a special microscope called an electron microscope, is the presence of microvillous inclusion bodies. Inside affected enterocytes, small clumps of abnormal microvilli mix with misplaced digestive proteins to form these inclusions^[2]. These inclusions are the hallmark of the disease and give it its name^[7].

Disease identification codes

P78.3
DA90.Y
619445; 251850
C0341306
C537470
7039
10068494
2290

Other names for this condition

Congenital microvillous atrophy, Congenital microvillus atrophy, Congenital enteropathy, Congenital familial protracted diarrhea with enterocyte brush-border abnormalities, Davidson disease, Familial protracted enteropathy, Intractable diarrhea of infancy, Microvillous atrophy, Microvillus atrophy, MVID

Associated anatomy

• Small intestine
• Intestinal epithelial cells (enterocytes)

Symptoms and clinical presentation

Signs of MVID usually show up within hours or days after birth^[1]. However, sometimes the symptoms show up later, around two to four months after birth, and may be less severe^[2]. Two clinical forms of MVID have been described: an early-onset form, developing within hours or days of birth, and a late-onset form, occurring in the first months of life^[4].

The main symptom is severe, watery diarrhea that doesn’t go away^[1]. Babies have profuse, intractable diarrhea, meaning it persists despite total bowel rest^[3]. This diarrhea leads to massive fluid loss. Due to high digestive losses, patients can lose up to 30 percent of their body weight in 24 hours, resulting in profound metabolic acidosis and severe dehydration^[11]. Stool production can be 100 to 500 milliliters per kilogram of body weight per day when the infant is fed, a volume comparable to or greater than that observed in cholera^[11].

Children with MVID cannot absorb the nutrients that they eat^[1]. This prevents the absorption of nutrients from food during digestion, resulting in malnutrition and dehydration^[2]. Food intake increases the frequency of diarrhea^[2]. The diarrhea is of the secretory type, meaning it persists even when fasting^[11].

Additional complications and symptoms may include:

• Life-threatening dehydration requiring hospitalization^[1]
• Poor weight gain and failure to gain weight properly^[1]
• Difficulty gaining weight and growing at the expected rate (failure to thrive)^[2]
• Developmental delay^[2]
• Liver and kidney problems^[2]
• Thinning of the bones (osteoporosis)^[2]
• Metabolic acidosis^[5]

Some affected individuals develop cholestasis, which is a reduced ability to produce and release a digestive fluid called bile. Cholestasis leads to irreversible liver disease (cirrhosis)^[2]. Long-term parenteral nutrition may be complicated with specific liver cholestasis^[4].

Pregnancy and birth are usually normal^[5]. Developmental delays may be present and rare associated abnormalities such as inguinal hernia and renal dysplasia have been reported^[4].

Causes and inheritance

MVID is inherited as an autosomal recessive genetic trait^[1]. This means that both parents must carry a copy of the affected gene in order to pass the disease on to their child^[1]. When both parents carry the faulty gene, there is a 1 in 4 chance with each pregnancy that the child will have the condition^[16]. In some families, more than one child is affected^[1]. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition^[2].

Several genes have been identified that are thought to be involved in MVID^[1]. The most common genetic cause is mutations in the MYO5B gene, which provides instructions for making a protein called myosin Vb^[2]. This protein helps to determine the position of various components within cells, a property known as cell polarity. Myosin Vb also plays a role in moving components from the cell membrane to the interior of the cell for recycling^[2].

MYO5B gene mutations that cause MVID result in a decrease or absence of myosin Vb function. In enterocytes, a lack of myosin Vb function changes the cell polarity. As a result, enterocytes cannot properly form structures called microvilli^[2]. Inside affected enterocytes, small clumps of abnormal microvilli mix with misplaced digestive proteins to form microvillous inclusions, which contribute to the dysfunction of enterocytes^[2].

Other genes known to cause MVID include:

• STX3 (Syntaxin 3 gene): A variant of the disorder, without microvillous inclusion vesicles, is caused by loss-of-function mutations in this gene^[4]
• STXBP2 (also called Munc18-2): When associated with hemophagocytic lymphohistiocytosis, the disease can also be caused by mutation of this gene^[4]
• UNC45A^[11]

The genes that have been identified include Myosin 5b and Syntaxin 3^[1]. Some patients do not display mutations in any identified gene^[4]. These cases may be variants of microvillous inclusion disease, but the causes are usually unknown^[2].

Mutations in these genes result in a polarization defect in the enterocyte and an accumulation of intracellular vesicles at the apical level due to impaired exocytosis. The main transporters and ion channels are therefore not present at the surface of the intestine, resulting in defective absorption and significant losses^[11]. Mutations disrupt trafficking between apical cargo vesicles and the apical plasma membrane. Thus, disturbed delivery of certain brush border membrane proteins is a common defect in MVID^[7].

How the disease is diagnosed

Diagnosing microvillous inclusion disease involves a number of steps^[1]. The diagnosis is suspected on the basis of clinical manifestations^[4]. First, doctors will test to determine the kind of diarrhea involved and which nutrients cannot be absorbed^[1].

If doctors suspect a congenital diarrhea, they will need to look at a sample of the tissue in the small intestine^[1]. 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 called biopsies^[1].

The diagnosis is confirmed by histological analysis of small intestine biopsies^[4]. Light microscopy shows accumulation of PAS-positive granules (positive to Schiff’s periodic acid staining) at the apical pole of immature enterocytes, together with an atrophic band indicating microvillous atrophy and, in parallel, an intracellular PAS or CD10 positive line marking the microvillous inclusion bodies^[3]. The biopsies reveal villous atrophy and abnormal inclusion material in the intestinal epithelium, without crypt hyperplasia^[4].

The appearance of microvillous inclusion disease on light microscopy is similar to celiac sprue; however, it usually lacks the intraepithelial lymphocytic infiltration characteristic of celiac sprue and stains positive for carcinoembryonic antigen (CEA)^[5]. The definitive diagnosis is dependent on electron microscopy^[5].

Using electron microscopy, doctors can detect the main features of microvillous inclusion disease, which are tiny but distinct differences in the cells of the small intestine^[1]. Electron microscopy reveals microvillous atrophy and in most cases, microvillous inclusion vesicles in the cytoplasm of enterocytes^[4]. Ultrastructural analyses reveal a partial to total atrophy of microvilli on mature enterocytes with apical accumulation of numerous secretory granules in immature enterocytes, and the highly characteristic inclusion bodies containing rudimentary or fully differentiated microvilli in mature enterocytes^[3].

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^[1]. Molecular genetic testing has become essential to confirm the diagnosis^[4].

Prenatal diagnosis is only possible if the specific genetic mutation has been identified in an affected family member^[11]. As MVID is a rare disease with no specific and systematic prenatal signs, prenatal diagnosis is not routinely available^[4].

The differential diagnosis includes rare congenital enteropathies such as autoimmune enteropathy, chloride diarrhea, congenital sodium diarrhea, and congenital tufting enteropathy^[4].

Treatment and management

There are currently no drug treatments for MVID^[1]. To date, there is no cure for the disease^[11]. Treatment is supportive and involves long-term maintenance of nutrition and hydration^[1].

Infants and children with this disease usually need specialized intravenous nutrition, called parenteral nutrition, in order to grow normally and avoid dehydration^[1]. In individuals with microvillous inclusion disease, lifelong nutritional support is needed and given through intravenous feedings^[2]. Management involves total parenteral nutrition for life, meaning the administration of daily nutritional intake by vein^[11].

To date, no curative therapy exists and children with MVID are totally dependent on parenteral nutrition^[3]. Long-term outcome is generally poor, due to metabolic decompensation, repeated states of dehydration, and infectious and liver complications related to the parenteral nutrition^[3]. While parenteral nutrition can temporarily stabilize a baby’s health, it is not an ideal long-term solution. Prolonged use of parenteral nutrition may lead to liver damage and elevate the susceptibility to infections^[21].

A variant of microvillous inclusion disease with milder diarrhea often does not require full-time parenteral nutrition. Individuals with the variant type frequently live past childhood^[2]. In some later-onset cases, partial oral absorption has been described^[4].

In instances where parenteral nutrition gives rise to complications, intestinal transplantation frequently emerges as the preferred alternative^[21]. When parenteral nutrition is no longer possible in the long term, intestinal transplantation, and if necessary, associated liver transplantation, may be considered^[11]. As MVID is a very rare disorder, which is extremely difficult to diagnose and manage, children with MVID should be transferred to specialized pediatric gastro-intestinal centers, if possible, a center equipped to perform small bowel transplantation^[3]. Early small bowel transplantation resulting in intestinal autonomy gives new hope for disease management and outcome^[3].

Recent research using patient-derived intestinal organoids has uncovered promising treatment approaches. Studies have shown that an existing chloride channel blocker called crofelemer reduced chloride and water secretion in organoids derived from MVID patients. This drug, currently approved for adult diarrhea caused by HIV or chemotherapy, recently obtained FDA permission to be tested in a clinical trial for MVID^[9]. Additionally, research has suggested that gamma-secretase inhibitors could potentially restore microvilli structure and function, though more specific pathways are being investigated to minimize side effects^[9].

How common is the disease

The prevalence of microvillous inclusion disease is unknown^[2]. MVID is a very rare disorder^[3]. Microvillous inclusion disease is extremely rare, however, no prevalence data have been published^[5].

At least 200 cases have been reported in Europe, although this condition occurs worldwide^[2]. Less than 200 cases have been reported to date^[4]. An estimate of a few hundred children with the disease in Europe has been made but no time frame to which this count applies is given^[5]. Prevalence is estimated at around 200 patients diagnosed in Europe, a figure that could rise with better knowledge of the disease and diagnostic tools^[11].

There is a male predominance, with a sex ratio of 1.5:1^[4]. Countries with higher degrees of consanguinity experience higher prevalence rates due to its autosomal recessive transmission^[5].

Until about 10 years ago, 50 percent of kids with MVID would die before age 2. Because of advances in parenteral nutrition, it has become a manageable disease. But children need parenteral nutrition every day and are still often in the hospital for dehydration and infections^[9].