Microvillus inclusion disease (MVID) is characterized by onset of intractable life-threatening watery diarrhea during infancy. Two forms are recognized: early-onset MVID with diarrhea beginning in the neonatal period, and late-onset, with first symptoms appearing after 3 or 4 ... Microvillus inclusion disease (MVID) is characterized by onset of intractable life-threatening watery diarrhea during infancy. Two forms are recognized: early-onset MVID with diarrhea beginning in the neonatal period, and late-onset, with first symptoms appearing after 3 or 4 months of life. Definite diagnosis is made by transmission electron microscopy demonstrating shortening or absence of apical microvilli with pathognomonic microvillus inclusions in mature enterocytes and peripheral accumulation of periodic acid-Schiff (PAS)-positive granules or vesicles in immature enterocytes (Muller et al., 2008). The natural course of MVID is often fatal, but partial or total weaning from parenteral nutrition has been described.
Davidson et al. (1978) described a group of infants who presented with an apparently familial enteropathy characterized by protracted diarrhea from birth and hypoplastic villus atrophy. Electron microscopic examination of surface enterocytes in a jejunal biopsy specimen from ... Davidson et al. (1978) described a group of infants who presented with an apparently familial enteropathy characterized by protracted diarrhea from birth and hypoplastic villus atrophy. Electron microscopic examination of surface enterocytes in a jejunal biopsy specimen from 1 of the patients showed peculiar intracytoplasmic inclusions composed of neatly arranged brush-border microvilli. Similar intracytoplasmic inclusions were described in other infants who had protracted diarrhea starting at or soon after birth (Phillips et al., 1985). Cutz et al. (1989) described the clinical and pathologic features of 9 cases. Three of the patients were from their original group of 5 patients reported by Davidson et al. (1978). Five were girls and four boys. Polyhydramnios was not observed in any of the patients, in contrast to congenital chloride diarrhea and diarrhea due to deficient sodium-hydrogen exchange, both of which are invariably associated with polyhydramnios. Three sets of sibs were represented among the 9 patients. In 2 families the parents were first cousins. One of the patients was still alive at 20 months; the other 8 had died at ages varying from 9 to 18 months. Cutz et al. (1989) concluded that this disorder may represent the most common cause of severe refractory diarrhea in the neonatal period. They suggested that microvillus inclusion disease may result from defective brush-border assembly and differentiation; it may represent an inborn error of intracellular transport, leading to aberrant assembly of the components of the enterocyte surface membrane. Rectal biopsy was proposed as a dependable and relatively easy method for early diagnosis. From a review of 23 cases of microvillus atrophy collected from medical centers around the world, Phillips and Schmitz (1992) concluded that congenital and late-onset forms could be identified and that cases of late onset appeared to have a better prognosis. They concluded that the first morphologic abnormality to be detected in the intestinal epithelium was accumulation of 'secretory granules'; microvillus inclusions were seen in older cells in the upper villus region. Phillips and Schmitz (1992) suggested that a fundamental defect affects the intracellular traffic of certain cell components. Their patients included 8 boys and 15 girls from 22 families, one family having 2 affected sisters. One Caucasian parental couple out of 15 was consanguineous and 5 Arab couples out of 6 were consanguineous. In 20 families in which information was available, more than 1 child was affected in 5. In 4 additional families, sibs had died from intractable diarrhea in the first months of life. In all but 3 cases, diarrhea was the only symptom during the first days of life. Fifteen infants (75%) died between 3 and 9 months, mostly of dehydration, malnutrition, and sepsis. The oldest patient at the time of survey was 5 years old and growing normally. Aspirin in low dosage decreased stool output in this patient. All patients were receiving total parenteral nutrition (TPN). Three of the patients still alive at the time of survey had 'late-onset' diarrhea. Fish and Molitoris (1994) discussed microvillus inclusion disease in connection with the role of changes in epithelial polarity in the pathogenesis of disease states. Likely possibilities for the mechanism of formation of these abnormal cytoplasmic vesicular bodies and apical surface membranes are centered around the abnormal delivery of Golgi-derived vesicles to the apical membrane. Processes mediated by both microtubules and actin microfilaments are involved in the delivery of vesicles to the apical region. Treatment of cultured fetal intestinal epithelium with microfilament-disrupting drugs resulted in the collapse of the apical membrane, with the formation of intracellular microvillus inclusion bodies (Carruthers et al., 1986). Intractable diarrhea of infancy (IDIF) was first defined by Avery et al. (1968) as a noninfectious diarrhea lasting for more than 2 weeks, with onset before a few months of age, with consequent malabsorption and failure to thrive. It comprises a heterogeneous group of conditions; while the great majority of cases have no known etiology, several reports distinguished ED2 subgroups. Straussberg et al. (1997) noted that in one subgroup, there is evidence of autoimmune involvement of the gastrointestinal tract as part of a systemic immune response. A second subgroup is characterized by a genetic basis, as indicated by parental consanguinity and a pattern of autosomal recessive inheritance. In this form, onset is usually before 2 months of age, extra intestinal involvement is infrequent, and there is no improvement of the diarrhea with diet and/or immunosuppression. Straussberg et al. (1997) reported a cluster of cases with Jewish Iraqi ancestry who showed no evidence of antienterocyte antibodies, did not respond to an elemental diet, steroid or immunosuppression therapy, and were dependent on total parenteral nutrition for years. Their 5 Iraqi Jewish patients with intractable diarrhea beginning during the first days of life belonged to 4 families. The parents were consanguineous in 3 families and the disorder recurred in a second sib in 1 family. The patients were all born after uneventful pregnancy and labor, with birth weight in the normal range. There were no dysmorphic features. Three patients were breastfed. Diarrhea was of the secretory type. Jejunal biopsies performed on all patients ranged from normal to severe partial villus atrophy. No similar cases were known in other ethnic groups in Israel, suggesting a possibly high gene frequency among Jews of Iraqi origin. Straussberg et al. (1997) concluded that the suggestion of a hereditary inborn defect of enterocyte differentiation as the pathogenetic mechanism is not certain and pointed out that the reports are probably based on a heterogeneous population of patients. In 4 patients from the Navajo reservation in northern Arizona, Pohl et al. (1999) observed microvillus inclusion disease with early onset. A fifth, unrelated affected Navajo child had been reported by Schofield et al. (1992).
Among 79 genes contained in the critical interval for MVID identified by Muller et al. (2008) using homozygosity mapping, MYO5B (606540) was considered a plausible candidate. The authors performed mutation analysis of the 40 MYO5B exons and all ... Among 79 genes contained in the critical interval for MVID identified by Muller et al. (2008) using homozygosity mapping, MYO5B (606540) was considered a plausible candidate. The authors performed mutation analysis of the 40 MYO5B exons and all splice sites in the proband of the linked family and identified a homozygous in-frame insertion (606540.0001). They then identified 6 distinct, homozygous germline MYO5B mutations in 6 of 9 additional probands. Each of the mutations segregated with disease status, and none was present among 188 controls. Two additional affected individuals had a heterozygous nonsense mutation, with no second mutation identified on the other allele; however, Muller et al. (2008) noted that direct sequencing might have missed larger deletions or intronic gene mutations. In 7 Navajo patients with severe, early-onset MVID, Erickson et al. (2008) identified a homozygous missense mutation (P660L; 606540.0006) in exon 16 of the MYO5B gene. Five obligate carriers were heterozygous for the mutation, which was not found in and 8 unrelated Navajos.