Clinical and biochemical features of different molecular etiologies of familial chylomicronemia

J Clin Lipidol. 2018 Jul-Aug;12(4):920-927.e4. doi: 10.1016/j.jacl.2018.03.093. Epub 2018 Apr 4.


Background: Familial chylomicronemia syndrome (FCS) is an ultra-rare phenotype that is usually caused by biallelic mutations in the LPL gene encoding lipoprotein lipase, or less often in APOC2, APOA5, LMF1, or GPIHBP1 genes encoding cofactors or interacting proteins.

Objectives: We evaluated baseline phenotypes among FCS participants in a phase 3 randomized placebo-controlled trial of volanesorsen (NCT02211209).

Methods: Baseline clinical, fasting, and postfat load metabolic markers were assessed. Targeted next-generation DNA sequencing plus custom bioinformatics was used to genotype subjects.

Results: Among 52 FCS individuals, 41 had biallelic LPL gene mutations (LPL-FCS patients): 82%, 7%, and 11% were missense, nonsense, and splicing variants, respectively. Eleven individuals had non-LPL-FCS; 2 had mutations in APOA5, 5 in GPIHBP1, and 1 each in LMF1 and APOC2 genes, respectively. Two other individuals were double heterozygotes, each with 1 normal LPL allele. All subjects had extremely high triglycerides (TGs) and chylomicrons, but very low levels of other lipoproteins. Compared with LPL-FCS individuals, non-LPL-FCS individuals were very similar for most traits, but had significantly higher postheparin LPL activity, higher 4-hour postprandial insulin and C-peptide levels; and higher low-density lipoprotein cholesterol levels. In non-LPL-FCS individuals compared to those with LPL-FCS, there were also nonsignificant trends toward lower levels of total and chylomicron TGs, lower 4-hour postprandial chylomicron TG levels, and higher very-low-density lipoprotein TG levels.

Conclusion: Thus, LPL FCS and non-LPL FCS are largely phenotypically similar. However, LPL FCS patients have lower postheparin LPL activity and a trend toward higher TGs, whereas low-density lipoprotein cholesterol was higher in non-LPL-FCS patients.

Keywords: Familial chylomicronemia syndrome; Genetic variation; Genetics; Hypertriglyceridemia; Lipolysis; Lipoprotein lipase; Next-generation DNA sequencing; Pancreatitis; Type I hyperlipoproteinemia; Volanesorsen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apolipoprotein A-V / genetics
  • Cholesterol, LDL / blood
  • Female
  • Humans
  • Hyperlipoproteinemia Type I / genetics
  • Hyperlipoproteinemia Type I / metabolism
  • Hyperlipoproteinemia Type I / pathology*
  • Lipoprotein Lipase / genetics*
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Polymorphism, Genetic
  • Receptors, Lipoprotein / genetics
  • Triglycerides / blood


  • APOA5 protein, human
  • Apolipoprotein A-V
  • Cholesterol, LDL
  • GPIHBP1 protein, human
  • LMF1 protein, human
  • Membrane Proteins
  • Receptors, Lipoprotein
  • Triglycerides
  • LPL protein, human
  • Lipoprotein Lipase

Supplementary concepts

  • Familial hyperchylomicronemia syndrome

Associated data


Grant support