Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an “FCS score”

Abstract

Familial chylomicronaemia syndrome (FCS) is a rare, inherited disorder characterised by impaired clearance of triglyceride (TG)-rich lipoproteins from plasma, leading to severe hypertriglyceridaemia (HTG) and a markedly increased risk of acute pancreatitis. It is due to the lack of lipoprotein lipase (LPL) function, resulting from recessive loss of function mutations in the genes coding LPL or its modulators. A large overlap in the phenotype between FCS and multifactorial chylomicronaemia syndrome (MCS) contributes to the inconsistency in how patients are diagnosed and managed worldwide, whereas the incidence of acute hypertriglyceridaemic pancreatitis is more frequent in FCS. A panel of European experts provided guidance on the diagnostic strategy surrounding FCS and proposed an algorithm-based diagnosis tool for identification of these patients, which can be readily translated into practice. Features included in this FCS score comprise: severe elevation of plasma TGs (fasting TG levels >10 mmol/L [885 mg/dL] on multiple occasions), refractory to standard TG-lowering therapies, a young age at onset, the lack of secondary factors (except for pregnancy and oral oestrogens) and a history of episodes of acute pancreatitis. Considering 53 FCS patients from three cohorts and 52 MCS patients from three cohorts, the overall sensitivity of the FCS score (≥10) was 88% (95% confidence interval [CI]: 0.76, 0.97) with an overall specificity of 85% (95% CI: 0.75, 0.94). Receiver operating characteristic curve area was 0.91. Pragmatic clinical scoring, by standardising diagnosis, may help differentiate FCS from MCS, may alleviate the need for systematic genotyping in patients with severe HTG and may help identify high-priority candidates for genotyping.

Spectrum of Mutations and Long-Term Clinical Outcomes in Genetic Chylomicronemia Syndromes

“…Indeed, it has been recently shown that fasting triglyceride levels >10 mmol/L (885 mg/dL) on multiple occasions, refractory to standard triglyceride-lowering therapies, a young age at onset, the lack of secondary factors, and a history of episodes of AP are powerful predictors of FCS. 3 In agreement with previous reports, 6 the most common molecular defect in FCS patients was represented by rare loss-of-function mutations in LPL gene. We detected 9 LPL mutations, 3 of which are already known to be causative of FCS 26 (https://www.omim.org/ entry/609708), whereas 4 were novel and 2 known but never associated to FCS phenotype.…”

“…Overall, these findings are consistent with the emerging model indicating that severe hypertriglyceridemia phenotype may be caused by the contribution of multiple alleles with large or minor effects interacting each others. 3 However, a clear explanation of mechanisms linking the increased burden of small-effect variants in triglyceride genes with the extreme elevation of plasma triglycerides is not available. Previous observations have highlighted the importance of alterations in the kinetic of LPL activation.…”

“…All other identified rare and low-frequency heterozygous variants were used for the MCS group classification. 2,3 Notably, the common variant p.R19W in APOA5 (rs3135506) was used for the molecular diagnosis of MCS if present both at homozygous and heterozygous state. [22][23][24] The patients were defined as undetermined if not carrying rare or low-frequency variants in any of the sequenced genes.…”

“…1 It is usually diagnosed when fasting plasma concentration of total triglycerides exceeds 10 mmol/L (≥885 mg/dL) on multiple occasions. 2,3 The clinical relevance of severe hypertriglyceridemia is due to its association with about 2-fold higher risk of acute pancreatitis (AP) 4 with a stepwise increase of this risk over time. 5 In addition to being a potentially life-threatening medical emergency, AP may also lead to several clinical complications such as chronic pancreatitis, pancreatic insufficiency, and type 2 diabetes mellitus.…”

“…8 Neurological symptoms, such as irritability, memory problems, dementia, and depression, have also been documented. 3 Typically, these patients have poor response to triglyceride-lowering medications so that their management represents a clinical challenge. 6 The cornerstone of the therapy of FCS is represented by a drastic reduction of fat intake (8%-10% of total calories), which is difficult to be maintained over time.…”