CHYLOMICRONEMIA SYNDROME

APOA5, APOC2, GPIHBP1, LMF1, LPL

Description

SCIENTIFIC BACKGROUND

Familial chylomicronemia syndrome (FCS, formerly type I hyperlipidemia) is a rare autosomal recessive inherited disorder of the chylomicron metabolism. Laboratory chemically, 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 mostly made in the context of recurrent pancreatitis (DD: hereditary pancreatitis), with eruptive xanthomas and hepatomegaly being other common phenotypic manifestations. A milk intolerance in childhood is frequently reported anamnestically. The therapy of pancreatitic symptoms consists of a low-fat diet and alcohol restriction. In particularly severe cases, lipid apheresis may be indicated.

 

Hepatic enzyme lipoprotein lipase (Lpl), which is present 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. Secondary, Lpl deficiency can be caused by pathogenic variants in the APOC2 gene, the major cofactor for Lpl. Furthermore, variants in the GPIHBP1 gene (glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1) leading to a defect of the transporter of lipoprotein lipase have been described. Additionally, variants in the LMF1 gene (lipase maturation factor-1) are associated with a combined lipase deficiency, or in rare cases with variants in the APOA5 gene. ApoA5 is involved in the hydrolysis of triglyceride-rich lipoproteins by increasing Lpl activity.

 

During therapy of 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 a solution of the enzyme from its heparin-sulfate binding sites prior to blood collection (post-heparin Lpl activity). Proper collection conditions must be ensured, as well as immediate freezing of the EDTA plasma sample 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

ASSOCIATED TESTS

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