Chylomicronaemia syndrome

Onset is usually in childhood with abdominal pain, acute pancreatitis, eruptive xanthomata, and hepatosplenomegaly. Approximately 25% of affected children develop symptoms before the age of one year and the majority before the age of ten years, although some individuals first present during pregnancy. Untreated plasma triglyceride concentrations characteristically exceed 2,000 mg/dL, and the plasma appears lactescent on standing, reflecting persistent fasting chylomicronaemia. When triglyceride concentrations exceed 4,000 mg/dL, the retinal arterioles, venules, and fundus may show the characteristic pale-pink appearance of lipemia retinalis. Pancreatitis episodes can be severe and are rarely complicated by total pancreatic necrosis. Recurrent acute pancreatitis is the dominant cause of morbidity, and clinical expression varies considerably between affected individuals, including within the same family, with the timing and severity of pancreatitis episodes accounting for the principal long-term clinical burden in affected individuals.

Chylomicronaemia syndrome is inherited in an autosomal recessive manner. Each child of two heterozygous carrier parents has a 25% risk of being affected, a 50% risk of being a heterozygous carrier, and a 25% chance of inheriting two wild-type alleles. Carrier testing of at-risk relatives requires prior identification of the familial pathogenic variants. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The FCS Score, an eight-item expert-panel clinical score with a cut-off of 10 points or more, establishes the clinical diagnosis when met. Plasma triglyceride concentrations above 2,000 mg/dL with lactescent (lipaemic) plasma in the untreated state, together with absent post-heparin lipoprotein-lipase activity, are diagnostic of familial LPL deficiency.

When treating hypertriglyceridemia with fibrates, which act by transcriptionally activating LPL gene expression, it is important to determine whether a functional LPL allele with residual activity is present. To determine LPL activity in vitro, the enzyme must be dissociated from its heparin sulphate binding sites prior to blood collection (post-heparin LPL activity). The appropriate blood collection conditions must be followed, and the EDTA plasma sample must be immediately frozen in dry ice or liquid nitrogen.

Main differential diagnoses include:

• Multifactorial chylomicronaemia syndrome (Fredrickson type V): polygenic small-effect variants with acquired secondary factors; far more common than FCS; APOA5, APOC3 and others.
• : mixed triglyceride and LDL-cholesterol elevation, variable lipoprotein phenotypes; USF1, APOA5, and LPL.
• Monogenic familial : severe hypertriglyceridaemia without obligate chylomicron predominance, heterozygous large-effect variants plus secondary factors; APOA5, LPL and others.

• Molecular genetic testing confirms the underlying cause and secures the diagnosis when biochemical findings are inconclusive.
• It informs specific and individualised surveillance and clinical management and is a prerequisite for targeted medical care decisions made by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variants are known, targeted testing of at-risk relatives can clarify their carrier or affected status and inform genetic counselling.

• Burnett JR, Hooper AJ, Hegele RA. Familial lipoprotein lipase deficiency. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. 2017 Jun 22. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1308/. PMID: .
• Bardey F, Rieck L, Spira D, März W, Binner P, Schwab S, et al. Clinical characterization and mutation spectrum of patients with hypertriglyceridemia in a German outpatient clinic. J Lipid Res. 2024;65(7):100589. doi:10.1016/j.jlr.2024.100589. PMID: . PMCID: PMC11913797.
• Moulin P, Dufour R, Averna M, Arca M, Cefalù AB, Noto D, et al. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): expert panel recommendations and proposal of an “FCS score”. Atherosclerosis. 2018;275:265-272. doi:10.1016/j.atherosclerosis.2018.06.814. PMID: .
• Ward NC, Chan DC, Watts GF. A tale of two new targets for hypertriglyceridaemia: which choice of therapy? BioDrugs. 2022;36(2):121-135. doi:10.1007/s40259-022-00520-2. PMID: . PMCID: PMC8986672.