Last updated: January 29, 2024
Introduction to Familial Chylomicronemia Syndrome (FCS)
Familial chylomicronemia syndrome (FCS) represents a family of related monogenic disorders that manifest with symptoms typical of the related, polygenic disorder simply termed chylomicronemia syndrome. FCS is primarily caused by autosomal recessive inheritance of mutations in the LPL gene which encodes the enzyme, lipoprotein lipase, LPL. This disorder is also referred to as one of the many forms of hyperlipoproteinemia. When the disorder results from mutations in the LPL gene it is also known as hyperlipoproteinemia, type I.
Chylomicronemia syndrome, refers to a disorder that is caused from minor genetic variants that collectively result in polygenic hypertriglyceridemia. In this context it is appropriate to term the disorder, multifactorial chylomicronemia syndrome. Originally, the polygenic form of chylomicronemia syndrome was identified as hyperlipidemia, type V.
In addition to mutations in the LPL gene, mutations in genes that encode regulators of LPL function also result in familial chylomicronemia syndrome. These LPL regulators are encoded by the APOC2, APOA5, LMF1, and GPIHBP1 genes which encode apoC-II (apoC-2), apoA-V (apoA-5), lipase maturation factor 1, and glycosylphosphatidylinositol-anchored HDL binding protein 1, respectively.
The LMF1 and GPIHBP1 encoded proteins are involved in the synthesis and maturation of LPL while the APOC2 and APOA5 encoded proteins are found in chylomicrons and VLDL and serve to activate LPL in the presence of phospholipid. In the context of LPL activation in the vasculature, the apoC-II protein is the more significant.
Most individuals manifesting with chylomicronemia have the multifactorial (polygenic) form of the disorder. When FCS is caused by mutations in the LPL gene the disorder is referred to as classic FCS.
Molecular Biology of FCS
Lipoprotein lipase is encoded by the LPL gene. The LPL gene is located on chromosome 8p21.3 and is composed of 10 exons that encode a 475 amino acid precursor protein. Expression of the LPL gene is restricted to adipose tissue, cardiac tissue, and skeletal muscle. Mutations in the LPL gene causing classic FCS occur on an order of 1 per 1,000,000. Mutations in the LPL gene causing classic FCS include point mutations, insertions, and deletions. Most commonly found mutations are missense mutation with the G188E (Gly to Glu mutation at codon 188), R243C, and N291S mutations being frequently detected.
Synthesis of LPL occurs on the rough endoplasmic reticulum (ER) within parenchymal cells of adipose tissue and of cardiac and skeletal muscle. As LPL is being synthesized, the activity of lipase maturation factor 1 (LMF1) is required for maturation of LPL and its migration through the secretory pathway.
The LMF1 gene is located on chromosome 16p13.3 and is composed of 15 exons that generate six alternatively spliced mRNAs, that collectively encode five distinct protein isoforms. One of the most common LMF1 mutations found in FCS patients is a nonsense mutation at codon 439 (Y439X).
LPL is then subsequently exocytosed from the parenchymal cell where it binds to heparin sulfated proteoglycans (HSPG) present on the surface of the cell facing the subendothelial spaces. The enzyme is then picked up and transported from the subendothelial spaces of the capillaries to the capillary endothelial cells via the action of glycosylphosphatidylinositol-anchored HDL binding protein 1 which is encoded by the GPIHBP1 gene. Functional LPL is a homodimer which remains associated with the apical (lumen) surface of the endothelial cells through its interactions with GPIHBP1.
The GPIHBP1 gene is located on chromosome 8q24.3 and is composed of 4 exons that generate two alternatively spliced mRNAs, both of which encode distinct protein isoforms. Mutations in the GPIHBP1 gene were originally characterized as the cause of hyperlipoproteinemia, type 1D. Numerous mutations in the GPIHBP1 gene have been identified in FCS patients, the vast majority of which are missense mutations.
In addition to the LMF1 and GPIHBP1 encoded proteins, members of the angiopoietin-like (ANGPTL) protein family are involved in the synthesis and maturation of lipoprotein lipase as described in detail in the Lipoproteins, Blood Lipids, and Lipoprotein Metabolism page.
The APOC2 gene is located on chromosome 19q13.32 and is composed of 4 exons that encode a 101 amino acid precursor protein. The APOC2 gene resides close to the APOA4 gene and there is a naturally occurring read-through transcript consisting of both mRNAs. Mutations in the APOC2 gene were originally characterized as the cause of hyperlipoproteinemia type IB. Mutations in the APOC2 gene found in FCS patients include missense mutations, frameshift mutations, and deletions.
The APOA5 gene is located on chromosome 11q23.3 and is composed of 4 exons that generate three alternatively spliced mRNAs, all of which encode the same 366 amino acid precursor protein. Mutations in the APOA5 gene were originally characterized as the cause of hyperlipoproteinemia type 5. Mutations in the APOA5 gene in FCS patients include missense and nonsense mutations. The most commonly observed mutation is the nonsense mutation at codon 139 (Q139X). FCS resulting from APOA5 mutations is inherited in an autosomal dominant manner.
Clinical Features of FCS
The characteristic feature of familial chylomicronemia syndrome, which is also characteristic of multifactorial chylomicronemia syndrome, is intermittent or persistent fasting chylomicronemia. The chylomicronemia, in turn, results in hypertriglyceridemia. The hypertriglyceridemia is defined as a serum triglyceride level in excess of 1,000 mg/dL (normal is <150 mg/dL). The disorder also predisposes affected individuals to acute pancreatitis. Additional clinical findings in FCS patients are eruptive xanthomas, episodic abdominal pain, hepatosplenomegaly, and lipemia retinalis (creamy white appearance in peripheral retinal vessels).
Diagnosis of FCS can be made in a patient whose blood work shows triglyceride levels >880 mg/dL for three consecutive assays. In addition, the triglyceride levels show little to no benefit from standard lipid-lowering therapies. A complete lipid panel test should also be performed to assay for hyperchylomicronemia. In addition to chylomicronemia and hypertriglyceridemia, the lipid profile of a patient with classic FCS will show HDL <40 mg/dL, total cholesterol likely to be high, with measurement of LDL complicated by the high levels of triglycerides.
In the course of correct diagnosis of FCS it is important to exclude any secondary causes of polygenic
hyperchylomicronemia as well as secondary hypertriglyceridemia. These other clinical situations can include poorly controlled type 2 diabetes, obesity, severe hypothyroidism, metabolic syndrome and its associated insulin resistance, systemic lupus erythematosus, and alcoholism.
Most patients with classic FCS will present with symptoms in very early childhood or young adulthood. The splenomegaly that can be present in patients with classic FCS is the result of splenic infiltration of macrophages that have sequestered fatty acids from the blood. Acute pancreatitis resulting from classic FCS is associated with a mortality rate ranging around 5% in children and from 5% to 30% in adults.
Treatment of FCS
Management of FCS focuses primarily on treating the pancreatitis due to the high morbidity and mortality associates with this condition. Patients with FCS need to adopt a very low fat diet where the total intake of fats represents less than 10%–15% of total calories. The lipid in FCS patients diets should be enriched in medium-chain triglycerides (MCT) since these do not require pancreatic lipase nor bile acids for digestions and the fatty acids that are released are delivered, form intestinal enterocytes, to the blood and are not packaged into chylomicrons.
Two drugs that have been approved by the US FDA for use in the treatment of various hyperlipidemias have been shown to provide benefit in classic FCS patients. The drug lomitapide (Juxtapid®), which is an inhibitor of microsomal triglyceride transfer protein (MTP; also abbreviated MTTP) has been used to treat classic FCS patients but with limited success. The drug volanesorsen (Waylivra®), which is an antisense oligonucleotide to the mRNA encoding apoC-III, has been found to reduce triglyceride levels in classic FCS patients on the order of 50%–80%. ApoC-III is an inhibitor of LPL-dependent and LPL-independent pathways in the clearance of triglyceride-rich lipoproteins by the liver. Thus, its inhibition leads to enhanced hepatic triglyceride clearance. Although approved for use by the European Union, the US FDA has rejected approval of volanesoren due to a high (25%) of trial participants developed thrombocytopenia. The EU approval of volanesoren is strictly for patients with documented FCS.