RESUMEN

Biallelic pathogenic variants of the Sar1b gene cause chylomicron retention disease (CRD) whose central phenotype is the inability to secrete chylomicrons. Patients with CRD experience numerous clinical symptoms such as gastrointestinal, hepatic, neuromuscular, ophthalmic, and cardiological abnormalities. Recently, the production of mice expressing either a targeted deletion or mutation of Sar1b recapitulated biochemical and gastrointestinal defects associated with CRD. The present study was conducted to better understand little-known aspects of Sar1b mutations, including mouse embryonic development, lipid profile, and lipoprotein composition in response to high-fat diet, gut and liver cholesterol metabolism, sex-specific effects, and genotype-phenotype differences. Sar1b deletion and mutation produce a lethal phenotype in homozygous mice, which display intestinal lipid accumulation without any gross morphological abnormalities. On high-fat diet, mutant mice exhibit more marked abnormalities in body composition, adipose tissue and liver weight, plasma cholesterol, non-HDL cholesterol and polyunsaturated fatty acids than those on the regular Chow diet. Divergences were also noted in lipoprotein lipid composition, lipid ratios (serving as indices of particle size) and lipoprotein-apolipoprotein distribution. Sar1b defects significantly reduce gut cholesterol accumulation while altering key players in cholesterol metabolism. Noteworthy, variations were observed between males and females, and between Sar1b deletion and mutation phenotypes. Overall, mutant animal findings reveal the importance of Sar1b in several biochemical, metabolic and developmental processes.

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RESUMEN

Chylomicron retention disease (CMRD), also known as Anderson's disease, is an autosomal recessive condition with a genetic mutation in the secretion associated Ras related GTPase 1B (SAR1B) gene, a protein coding gene. CMRD classically manifests as steatorrhea, vomiting, failure to thrive or abdominal bloating shortly after birth or in childhood. Here, we report a rare case of a 50-day-old male infant who was, at first, overseen as a case of acute gastroenteritis with sepsis owing to the non-specific symptoms i.e. multiple episodes of loose stools with a low-grade fever and failure to thrive, and was managed accordingly. However, the symptoms did not resolve; moreover, the clinical condition deteriorated. Later, lipid profile, clinical presentation and pathological features led to a presumptive diagnosis of CMRD. Our patient showed significant improvement when treated with a trial of medium- and short-chain fatty acids. We conclude that, in resource-restricted countries, a therapeutic trial with the dietary changes is essential to not only prevent the devastating complication but also support the diagnosis.

RESUMEN

BACKGROUND: Intestinal lipid malabsorption, resulting from an impaired formation or secretion of chylomicrons and associated with severe hypobetalipoproteinemia (HBL), may be due to biallelic mutations in APOB (homozygous FHBL type-1), MTTP (abetalipoproteinemia), or SAR1B (chylomicron retention disease). OBJECTIVE: We investigated four children, each born from consanguineous parents, presenting with steatorrhea, malnutrition, accumulation of lipids in enterocytes, and severe hypocholesterolemia with an apparent recessive transmission. METHODS: We sequenced a panel of genes whose variants may be associated with HBL. RESULTS: Case 1, a 9-month-old male, was found to be homozygous for a SAR1B variant (c.49 C>T), predicted to encode a truncated Sar1b protein devoid of function (p.Gln17*). Case 2, a 4-year-old male, was found to be homozygous for a SAR1B missense variant [c.409 G>C, p.(Asp137His)], which affects a highly conserved residue close to the Sar1b guanosine recognition site. Case 3, a 6-year-old male, was found to be homozygous for an ∼6 kb deletion of the SAR1B gene, which eliminates exon 2; this deletion causes the loss of the ATG translation initiation codon in the SAR1B mRNA. The same homozygous mutation was found in an 11-month-old child (case 4) who was related to case 3. CONCLUSIONS: We report 4 children with intestinal lipid malabsorption were found to have chylomicron retention disease due to 3 novel variants in the SAR1B gene.

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RESUMEN

Chylomicron retention disease, also known as Anderson's disease, is a rare hereditary hypocholesterolemic disorder, recessive inherited, characterized by nonspecific symptoms as abdominal distension, steatorrhea, and vomiting associated with failure to thrive. We describe a patient with failure to thrive, chronic diarrhea and steatorrhea who the diagnosis of chylomicron retention disease was established after several months of disease progression. The genetic study confirmed a homozygosity mutation in SAR1B gene, identifying a mutation never previous described [c.83_84delTG(p.Leu28Argfs*7)]. With this case report the authors aim to highlight for this very rare cause of failure to thrive and for the importance of an attempting diagnosis, in order to start adequate management with low fat diet supplemented with fat-soluble vitamins, reverting the state of malnutrition and avoiding possible irreversible and desvantating complications.

RESUMEN

Chylomicron retention disease, also known as Anderson's disease, is a rare hereditary hypocholesterolemic disorder, recessive inherited, characterized by nonspecific symptoms as abdominal distension, steatorrhea, and vomiting associated with failure to thrive. We describe a patient with failure to thrive, chronic diarrhea and steatorrhea who the diagnosis of chylomicron retention disease was established after several months of disease progression. The genetic study confirmed a homozygosity mutation in SAR1B gene, identifying a mutation never previous described [c.83_84delTG(p.Leu28Argfs*7)]. With this case report the authors aim to highlight for this very rare cause of failure to thrive and for the importance of an attempting diagnosis, in order to start adequate management with low fat diet supplemented with fat-soluble vitamins, reverting the state of malnutrition and avoiding possible irreversible and desvantating complications.

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