Background
Microvillus inclusion disease (also referred to as congenital microvillus atrophy) is, with Tuft enteropathy, the best known disease of the intestinal epithelium causing intractable diarrhea of infancy, and a leading cause of secretory diarrhea in the first weeks of life. A group of infants with a familial enteropathy characterized by protracted diarrhea from birth and villus hypoplastic atrophy had been described in 1978 by Davidson et al. [1] The term microvillus atrophy was first used to identify the disease in 1982. The typical clinical presentation is watery profuse secretory diarrhea starting in the first hours of life. The peak age of onset is the early neonatal period. Although later-onset cases have been described, cases have never been described beyond the first 2-3 months of life.
Three variants of the disease have been identified: Microvillus inclusion disease, late-onset microvillus inclusion disease, and atypical microvillus inclusion disease.
In microvillus inclusion disease, diarrhea starts in the first few days of life and is immediately life threatening. Oral alimentation in nutritionally significant amounts is impossible. In late-onset microvillus inclusion disease, diarrhea starts later in life, usually in the second month. Diarrhea tends to be less severe than in the other form, and some alimentation is possible. A few cases have been termed atypical microvillus inclusion disease, in which the onset can be congenital or late, but the histologic picture is different.
The hallmark of the disease is the electron microscopic finding of disrupted enterocyte microvilli (ie, digitations of the apical membrane of the intestinal epithelial cell protruding into the lumen) and the appearance of characteristic inclusion vacuoles, the inner surfaces of which are lined by typical microvilli. Both lesions are seen only on electronic microscopy. In a notable percentage of consanguineous families, more than one child is affected; therefore, the disease appears to be transmitted as an autosomal recessive trait.
Pathophysiology
The pathogenesis of the disease, that had remained elusive for a long time, appears now to be associated with patient-unique, family-unique, and ancestry-unique mutations in the MYO5B gene, encoding the actin-based motor protein myosin Vb.
These mutations lead to severe perturbation of the microvillar cytoskeleton disrupting the transport of brush border components that have to be assembled at the apical membrane.
Biopsy samples from the small intestine of 2 infants with congenital microvillus inclusion disease were examined to analyze the membrane protein of the brush border. The samples demonstrated striking diminutions of the myosin bands. The genetic defect appears likely to cause abnormal binding of the myosin to the actin cable. In one patient with late-onset microvillus atrophy, the molecular defect involved a different protein, supposedly identified as vinculin.
Other studies have suggested an alternative hypothesis, namely that a defect in the autophagocytosis pathway [2] or an increase in enterocyte apoptosis and proliferation [3] explains the abnormalities observed in congenital microvillous disease.
Recently, Dutch investigators have found [4] that the mild variant of microvillus inclusion disease appears to be caused by loss of function of syntaxin 3 (STX3), an apical receptor involved in membrane fusion of apical vesicles in enterocytes. In fact, whole-exome sequencing of DNA from patients with variant microvillus inclusion disease revealed homozygous truncating mutations in STX3; and in addition, patient-derived organoid cultures and overexpression of truncated STX3 in CaCo2 cells recapitulated most characteristics of variant microvillus inclusion disease.
The postulated abnormality in the cytoskeleton causes a block in exocytosis, mainly of periodic acid-Schiff (PAS)–positive material (eg, polysaccharides, glycoproteins, glycolipids, neutral mucopolysaccharides). As a consequence, small secretory granules that contain a PAS-positive material accumulate in the apical cytoplasm of epithelial cells.
Substantial progress has been made in identifying the molecular nature of the secretory granules. A neutral, blood group antigen–positive glycosubstance that contains acetylated sialic acid accumulates in these granules. Acetylated sialic acid has been identified as a common component of the glycocalyx, suggesting that microvillus atrophy involves a defect in exocytosis of the glycocalyx or some of its components. To support this possibility, immunoreactivity against glycocalyx is found in secretory granules in microvillus atrophy.
The microvilli in the brush border are scanty, disorganized, and short.
Because of these alterations, mature enterocytes inefficiently absorb ions and nutrients, causing a malabsorption syndrome; however, the diarrhea is caused mainly by active secretion of water and electrolytes in the intestinal lumen (secretory diarrhea). The pathogenesis of the secretory diarrhea is unknown; it is assumed to result from an unbalance between decreased absorption and unaltered secretion. Data suggest that the morphologic changes of the disease result in a secondary decrease in the amount of messenger RNA (mRNA) encoding for apical membrane-transport systems.
Epidemiology
Frequency
United States
A cluster of cases from the Navajo reservation in northern Arizona suggests an incidence as high as 1 case per 12,000 live births.
International
A survey completed in 1987 among centers known for their involvement in pediatric gastroenterology identified more than 30 cases worldwide. Additional cases were later published, including a series of 17 cases from the United Kingdom between 1990-2008 [5] . Typical microvillus inclusion disease accounts for 80% of cases. The remaining 20% are due to mainly late-onset disease.
To better define this rare condition and its prevalence worldwide, an online MOLGENIS-based international patient registry has been constructed. [6] This easily accessible database currently contains detailed information of 137 patients with microvillus inclusion disease together with reported clinical/phenotypic details and 41 unique MYO5B mutations, several of which unpublished.
Mortality/Morbidity
The survival of patients with typical cases depends on total parenteral nutrition (TPN). Most infants of early series died when aged 3-9 months. The leading causes of death were dehydration, malnutrition, and sepsis.
Successful outcomes of small intestinal transplantation have been reported, and evidence suggests that an early transplant might be beneficial. [7, 8, 9] However, the prognosis remains poor, with most patients dying by the second decade of life as a result of complications of parenteral alimentation. Even patients who have undergone small-bowel transplantation have a mean 5-year survival rate of about 50%. Patients with late-onset or variant microvillus inclusion disease appear to have an improved prognosis.
Sex
A female preponderance has been observed among the published cases, with a female-to-male ratio of 2:1.
Age
The classic form of microvillus inclusion disease appears in the first 72 hours of life (usually on the first day) and is immediately life threatening. Late-onset microvillus atrophy starts after 6-8 weeks in a normal-appearing infant.
