SCIENTIFIC BACKGROUND

APOA5, APOC2, GPIHBP1, LMF1, LPL

SCIENTIFIC BACKGROUND

Familial chylomicronemia syndrome (FCS, formerly type I hyperlipidemia) is a rare autosomal recessive inherited disorder of chylomicron metabolism. In the laboratory, the disorder is characterized by severely elevated serum concentrations of triglycerides (up to 30,000 mg/dl) and a milky, creamy serum. A diagnosis is usually made in connection with recurrent pancreatitis (DD: hereditary pancreatitis). Eruptive xanthomas and hepatomegaly are other common phenotypic manifestations, and a milk intolerance in childhood is frequently reported in the patient's medical history. Treating pancreatic symptoms includes following a low-fat diet and alcohol restriction. In particularly severe cases, lipid apheresis may be indicated as treatment.

 

Hepatic enzyme lipoprotein lipase (Lpl), which is found on the endothelial cells of extrahepatic capillaries, plays an important role in the hydrolytic degradation of triglyceride-rich lipoproteins, particularly chylomicrons. FCS is caused by homozygous or mixed heterozygous pathogenic variants in the LPL gene. Lpl deficiency can also be caused by pathogenic variants in the APOC2 gene, which is the major cofactor for Lpl. Furthermore, variants in the GPIHBP1 gene (glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1) that lead to a defect in the transport of lipoprotein lipase have been described. Additionally, variants in the LMF1 gene (lipase maturation factor-1), or in rare cases variants in the APOA5 gene, are associated with a combined lipase deficiency . ApoA5 is involved in the hydrolysis of triglyceride-rich lipoproteins by increasing Lpl activity.

 

When treating hypertriglyceridemia with fibrates that act via transcriptional activation of Lpl gene expression, it is important to consider whether a functional LPL allele is present, possibly with residual activity. Determining Lpl activity in vitro requires separation of the enzyme from its heparin-sulfate binding sites prior to blood collection (post-heparin Lpl activity). Proper collection conditions are necessary, and the EDTA plasma sample must be immediately frozen in dry ice or liquid nitrogen.

 

References

Blom et al. 2018, J Clin Lipidol. 12:1234 / Stroes et al. 2017, Atheroscler Suppl. 23:1 / Burnett et al. 2017, GeneReviews® [Internet], www.ncbi.nlm.nih.gov/books/NBK1308/ / Custodis et Laufs 2011, Dtsch Med Wochenschr 136:1533 / Young et al. 2011, J Lipid Res 52:1869

GENES

APOA5, APOC2, GPIHBP1, LMF1, LPL
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