Rare diseases: microvilli inclusion disease (MVID), or microvillar atrophy (MVA)
Included microvilli disease is a rare disease that manifests itself in newborns with abundant watery diarrhoea
It is cured by feeding these babies for life exclusively by the venous route (parenteral nutrition).
Microvilli inclusion disease (MVID) also called microvilli atrophy (MVA) is a genetic disorder of the intestine caused by an alteration of the intestinal mucosa and in particular of the apical border (outer border or brush border) of the enterocytes, i.e. the cells of the intestinal wall that line the intestinal villi and whose function is to absorb nutrients.
It was first described in 1978 and is characterised by the appearance in infancy (early-onset form) of persistent watery diarrhoea that does not pass despite complete intestinal rest.
Cases have also been described occurring later, after the first two to three months of life (late-onset form).
Included microvilli disease is an extremely rare congenital disease
There are only a few hundred children with MVID in Europe.
The frequency is highest in countries with a high degree of inbreeding, which suggests autosomal recessive transmission.
Most patients with early onset have an alteration (mutation) in the MYO5B gene, a gene that contains the instructions to produce myosin Vb, which is involved in the transport of molecules and particles within the cell and in the growth of microvilli.
In children with late-onset microvilli disease, the STX3 gene is altered (mutated), which contains the instructions to produce syntaxin 3, a protein involved in maintaining cell polarity, which is essential for directing the transport of nutrients within the enterocytes (the cells that line the gut).
Both forms of the disease are inherited on an autosomal recessive basis: both copies of the genes, the one of maternal and paternal origin, are altered (mutated).
The parents carry only one copy of the altered gene and are not sick, but they risk with each pregnancy (25% chance) having a child with microvilli disease included
The pregnancy and delivery of sick children are generally normal.
The most suggestive symptom is severe watery diarrhoea that begins in the first few days of life and becomes so profuse that within the first 24 hours of life up to 30% of body weight is lost, resulting in severe dehydration.
This is often life-threatening as faecal losses are considerable (from 150 to over 300 ml/kg/day) and contain a very high proportion of sodium (approximately 100 mmol/L).
Complete and prolonged intestinal rest (fasting) can reduce stool volume, but not normalise it: losses, even on an empty stomach, almost always remain above 150 ml/kg/day.
When the disease appears in the first few days of life, there may therefore be an alteration in renal function caused not only by severe dehydration, but also by renal involvement of the disease: the renal tubular epithelia present the same polarisation defect as the intestinal epithelium.
However, renal involvement tends to be reduced later or to persist in the form of nephrocalcinosis (excessive renal calcium deposits) caused by dehydration.
In some children, liver function may also be impaired due to altered polarisation within the endothelial cells lining the bile ducts.
This can cause stasis of the bile produced by the liver and considerable itching caused by the high concentration of bile acids in the blood, which cannot be eliminated via the bile ducts.
The large losses of fluid with the faeces mean that all children with microvilli disease included require urgent supplementation of water and salts and intravenous replacement nutrition (parenteral nutrition).
Suspicion of microvilli inclusions disease is clinical in the case of an infant or young child with profuse diarrhoea who rapidly develops metabolic acidosis (accumulation of acids in the body) and signs of hypotonia (decreased muscle strength) with dehydration.
No other symptoms are associated with this disorder, however most children are also at risk of developing cholestasis (stasis of bile that cannot flow from the liver to the intestine) and liver failure.
An endoscopy of the digestive tract with intestinal biopsies is performed, which is the cornerstone for the diagnosis of microvilli disease included
Histological analysis, however, must be conducted with both light and electron microscopes.
Direct endoscopic analysis of the entire gastro-intestinal tract is in fact completely normal, apart from minor non-specific changes such as slight reddening of the mucosa or, in rare cases, indirect signs of villous atrophy.
In contrast, histological analysis reveals specific changes (mainly in the small intestine and, to a lesser extent, the colon).
Standard histology (under the light microscope) shows a variable degree of atrophy (poor development) of the villi (the mucosa appears as ‘thin mucosa’).
The other characteristic feature is the accumulation of granules in the apex of immature enterocytes.
On electron microscopy, the enterocytes show characteristic inclusion bodies (the ‘included microvilli’).
The diagnosis of included microvilli disease is difficult and should be treated or at least confirmed by particularly experienced pathologists
Inclusionary microvilli disease must be differentiated from intestinal epithelial dysplasia or ‘clumpy’ enteropathy, early-onset inflammatory diseases and autoimmune enteropathies, as well as from other forms of early-onset intractable diarrhoea (chlorohydorrhoea and congenital sodiorrhoea glucose-galactose malabsorption diarrhoea, sucrase-isomaltase deficiency diarrhoea) and more rarely by other forms of intestinal failure (chronic intestinal pseudo-obstruction, for example, or other forms of altered intestinal motility).
The most common complications of including microvilli disease, a consequence of severe diarrhoea, are acute episodes of dehydration and metabolic decompensation.
The decrease in blood volume caused by dehydration can lead to temporary ischaemia (insufficient blood supply to the brain) with more or less severe neurological and psychological outcomes and a delay in cognitive development.
For the same reason, kidney function can also be impaired.
Parenteral nutrition in this case is a true life-saving therapy and must be prepared and administered by personnel with extensive experience, especially in the initial stabilisation phase of the little ones, which often involves continuous adjustments in the volume and composition of the nutritional bags that are to be infused.
The main complications of parenteral nutrition and severe chronic intestinal failure, which are characteristic of this disease, are cholestasis (defects in bile elimination) and/or liver failure.
Hepatic impairment is preventable by conducting careful parenteral nutrition according to guidelines that advise avoiding excess calories and paying attention to the choice of the most appropriate lipid formulations.
Cholestasis, if associated with the underlying disease and therefore present already in the first months of life, will inexorably worsen over time
Other complications to watch out for are infectious complications, caused by central venous catheter-related sepsis, and thrombotic complications.
These complications may prevent parenteral nutrition and possibly suggest the advisability of a bowel transplant or a combined liver-intestine transplant.
To date, there is no decisive treatment for microvilli disease including
Anti-inflammatory drugs, including steroids and antisecretory drugs (sandostatin or loperamide), do not significantly modify diarrhoea and faecal losses.
Patients’ very survival depends on parenteral nutrition, which must be started early as it is the only means of stabilising them and preventing death from metabolic decompensation.
It is important, therefore, that children with suspected included microvilli disease are transferred to highly specialised paediatric gastroenterology centres as soon as possible.
Parenteral nutrition must be carried out for a very long time and is currently the only alternative to intestinal transplantation.
The latter can be performed as an isolated intestine transplant or a combined liver-intestine transplant.
However, the use of transplantation is only indicated when one is faced with serious complications of parenteral nutrition that make its continuation unsafe (nutritional insufficiency).
In the largest Italian and European case histories, the long-term survival of parenteral nutrition patients is superior to that of transplant patients.
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