BackgroundAnderson's disease (AD) or chylomicron retention disease (CMRD) is a very rare hereditary lipid malabsorption syndrome. In order to discover novel mutations in the SAR1B gene and to evaluate the expression, as compared to healthy subjects, of the Sar1 gene and protein paralogues in the intestine, we investigated three previously undescribed individuals with the disease.MethodsThe SAR1B, SAR1A and PCSK9 genes were sequenced. The expression of the SAR1B and SAR1A genes in intestinal biopsies of both normal individuals and patients was measured by RTqPCR. Immunohistochemistry using antibodies to recombinant Sar1 protein was used to evaluate the expression and localization of the Sar1 paralogues in the duodenal biopsies.ResultsTwo patients had a novel SAR1B mutation (p.Asp48ThrfsX17). The third patient, who had a previously described SAR1B mutation (p.Leu28ArgfsX7), also had a p.Leu21dup variant of the PCSK9 gene. The expression of the SAR1B gene in duodenal biopsies from an AD/CMRD patient was significantly decreased whereas the expression of the SAR1A gene was significantly increased, as compared to healthy individuals. The Sar1 proteins were present in decreased amounts in enterocytes in duodenal biopsies from the patients as compared to those from healthy subjects.ConclusionsAlthough the proteins encoded by the SAR1A and SAR1B genes are 90% identical, the increased expression of the SAR1A gene in AD/CMRD does not appear to compensate for the lack of the SAR1B protein. The PCSK9 variant, although reported to be associated with low levels of cholesterol, does not appear to exert any additional effect in this patient. The results provide further insight into the tissue-specific nature of AD/CMRD.
IP is an uncommon but almost certainly underrecognized lesion in children, and may be the cause of digestive and respiratory symptoms in some children.
A 6-month-old baby was hospitalized for repetitive episodes of abdominal distention, chronic diarrhoea with fatty stools and failure to thrive. Laboratory tests indicated normal stool fat content but a very low level of vitamin E (1 lmol/l). Exocrine pancreatic deficiency was ruled out. Total cholesterol, high density lipoprotein (HDL, 0AE49 mmol/l) and low density lipoprotein (LDL) (1AE44 mmol/l) and A1 and B apolipoproteins levels were decreased but triglycerides were in the normal range. No plasma chylomicrons could be found after a fat load. Electrophoresis of lipoproteins demonstrated low alpha (HDL) and beta lipoprotein (LDL) levels. Video-endoscopy showed the typical appearance of 'white hoary frosting', with fat loaded enterocytes being shown on ultrastructural studies. Blood count did not reveal any quantitative abnormalities but acanthocytes were observed on the smear (around 5% of total red blood cells) some with bizarre shapes. Anderson's disease was suspected and a mutation in the SAR1B gene was identified in exon 3. A low fat diet and parenteral fat-soluble vitamins with lipids infusions were initiated.Abnormalities of lipid metabolism associated with acanthocytosis are mainly acquired disorders but are rarely caused by primary hypocholesterolaemia, which includes abetalipoproteinemia, familial hypobetalipoproteinemia and Anderson's disease. Acanthocytosis is usually mild in Anderson's disease (<5% of red cells), haemolysis is often mild and anaemia may be absent. Several mutations in SAR1B are associated with fat malabsorption. The mechanism for red cell deformation is related to the disruption of lipid exchange between the red cell membrane and plasma with an increased cholesterol/phospholipid ratio leading to excessive rigidity of the red cells and preferential expansion of the outer leaflet of the lipid bilayer.
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