Chylomicron retention disease: genetics, biochemistry, and clinical spectrum

Abstract

Purpose of review Chylomicron retention disease (CRD) is an autosomic recessive disorder, in which intestinal fat malabsorption is the main cause of diverse severe manifestations. The specific molecular defect was identified in 2003 and consists of mutations in the SAR1B or SARA2 gene encoding for intracellular SAR1B GTPase protein. The aim of this review is first to provide an update of the recent biochemical, genetic and clinical findings, and second to discuss novel mechanisms related to hallmark symptoms. Recent findings CRD patients present with SAR1B mutations, which disable the formation of coat protein complex II and thus blocks the transport of chylomicron cargo from the endoplasmic reticulum to the Golgi. Consequently, there is a total absence of chylomicron and apolipoprotein B-48 in the blood circulation following a fat meal, accompanied by a deficiency in liposoluble vitamins and essential fatty acids. The recent discovery of Transport and Golgi organization and Transport and Golgi organization-like proteins may explain the intriguing export of large chylomicron, exceeding coat protein complex II size. Hypocholesterolemia could be accounted for by a decrease in HDL cholesterol, likely a reflection of limited production of intestinal HDL in view of reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I protein. In experimental studies, the paralog SAR1A compensates for the lack of the SAR1B GTPase protein. Summary Molecular testing for CRD is recommended to distinguish the disease from other congenital fat malabsorptions, and to early define molecular aberrations, accelerate treatment, and prevent complications.

Chylomicron Retention Disease: Failure to Thrive and Abdominal Distention in an Infant

“…Chylomicron retention disease is a recessively inherited, rare lipid malabsorption disorder that results from mutations in SARA2 and SAR1B genes ( 1 , 2 ). These genes encode for the SAR1B GTPase protein, which is necessary for the transport of prechylomicron vesicles from the endoplasmic reticulum to the golgi apparatus and for the fusion of these vesicles to the golgi apparatus.…”

Rare primary dyslipidaemias associated with low LDL and HDL cholesterol values in Portugal

“…Chylomicron retention disease, or Anderson’s disease, is a rare autosomal recessive disorder caused by biallelic loss-of-function alterations in the SAR1B gene that leads to failure of chylomicron secretion from enterocytes ( Hooper et al, 2005 ; Levy et al, 2019 ). Often, failure to thrive is observed in childhood, along with severe malabsorption, steatorrhea, and fat-soluble vitamin deficiency ( Levy et al, 2019 ). Homozygous patients have absence of apo B-48 and chylomicrons, and heterozygous subjects presents normal lipid profiles ( Hegele et al, 2020 ).…”

“…SAR1B, as the GDP-to-GTP exchanger, is a critical element in the final step of assembling this vesicular transport complex. Consequently, alterations in this gene affect pre-chylomicron trafficking from the ER to the Golgi apparatus, leading to the absence of chylomicrons and a marked accumulation of lipids in enterocytes ( Georges et al, 2011 ; Levy et al, 2019 ).…”

Abetalipoproteinemia Due to a Novel Splicing Variant in MTTP in 3 Siblings

“… 1 , 5 , 6 Mild hemolytic anemia develops secondary to acanthocytosis. The differential diagnosis of ABL includes homozygous hypobetalipoproteinemia 1 , 5 and chylomicron retention disease 7 due to biallelic rare mutations in the APOB and SAR1B genes, respectively. These conditions can be differentiated from ABL using both biochemical analyses and diagnostic DNA sequencing.…”