Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

Familial chylomicronemia syndrome: case reports of siblings with deletions of the GPIHBP1 gene.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare monogenic form of severe hypertriglyceridemia, caused by mutations in genes involved in triglyceride metabolism. Herein, we report the case of a Korean family with familial chylomicronemia syndrome caused by compound heterozygous deletions of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). CASE PRESENTATION: A 4-year-old boy was referred for the evaluation of severe hypertriglyceridemia (3734 mg/dL) that was incidentally detected 4 months prior. His elder brother also demonstrated an elevated triglyceride level of 2133 mg/dL at the age of 9. Lipoprotein electrophoresis revealed the presence of chylomicrons, an increase in the proportion of pre-beta lipoproteins, and low serum lipoprotein lipase levels. The patient's parents and first elder brother had stable lipid profiles. For suspected FCS, genetic testing was performed using the next-generation sequencing-based analysis of 31 lipid metabolism-associated genes, which revealed no pathogenic variants. However, copy number variant screening using sequencing depth information suggested large heterozygous deletion encompassing all the coding exons of GPIHBP1. A real-time quantitative polymerase chain reaction was performed to validate the deletion site. The results showed that the siblings had two heterozygous copy number variants consisting of the whole gene and an exon 4 deletion, each inherited from their parents. During the follow-up period of 17 months, the patient did not develop pancreatitis, following dietary intervention. CONCLUSION: These siblings' case of familial chylomicronemia syndrome caused by rare GPIHBP1 deletions highlight the implementation of copy number variants-beyond next-generation sequencing-as an important consideration in diagnosis. Accurate genetic diagnosis is necessary to establish the etiology of severe hypertriglyceridemia, which increases the risk of pancreatitis.

Acute pancreatitis risk in multifactorial chylomicronemia syndrome depends on the molecular cause of severe hypertriglyceridemia.

BACKGROUND AND AIMS: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the presence of heterozygous pathogenic variants (PVs) in TG-related metabolism genes or by accumulation of common variants in hyperTG susceptibility genes. This study aims to determine if the risk of AP is similar amongst MCS patients with different molecular causes of severe hyperTG. METHODS: This study included 114 MCS patients who underwent genetic testing for PVs in TG-related metabolism genes and 16 single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes. A weighted TG-polygenic risk score (TG-PRS) was calculated. A TG-PRS score ≥ 90th percentile was used to define a high TG-PRS. RESULTS: Overall, 66.7% of patients had severe hyperTG of polygenic origin. MCS patients with only a PV and those with both a PV and high TG-PRS were more prone to have maximal TG concentration ≥ 40 mmol/L (OR 5.33 (1.55-18.36); p = 0.008 and OR 5.33 (1.28-22.25); p = 0.02), as well as higher prevalence of AP (OR 3.64 (0.89-14.92); p = 0.07 and OR 11.90 (2.54-55.85); p = 0.002) compared to MCS patients with high TG-PRS alone. CONCLUSIONS: This is the first study to show that MCS caused by a high TG-PRS and a PV is associated with higher risk of AP, similar to what is seen in the monogenic form of severe hyperTG. This suggests that determining the molecular cause of severe hyperTG could be useful to stratify the risk of pancreatitis in MCS.

Validation of the familial chylomicronaemia syndrome (FCS) score in an ethnically diverse cohort from UK FCS registry: Implications for diagnosis and differentiation from multifactorial chylomicronaemia syndrome (MCS).

BACKGROUND AND AIMS: Prognosis and management differ between familial chylomicronaemia syndrome (FCS), a rare autosomal recessive disorder, and multifactorial chylomicronaemia syndrome (MCS) or severe mixed hyperlipidaemia. A clinical scoring tool to differentiate these conditions has been devised but not been validated in other populations. The objective of this study was to validate this score in the UK population and identify any additional factors that might improve it. METHODS: A retrospective validation study was conducted using data from 151 patients comprising 75 FCS and 76 MCS patients. All participants had undergone genetic testing for genes implicated in FCS. Validation was performed by standard methods. Additional variables were identified from clinical data by logistic regression analysis. RESULTS: At the recommended FCS score threshold ≥10 points, the sensitivity and specificity of the score in the UK population were 96% and 75%, respectively. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.88 (95% CI 0.83-0.94, p < 0.001). This study identified non-European (predominantly South Asian) ethnicity, parental consanguinity, body mass index (BMI) < 25 kg/m2, and recurrent pancreatitis as additional positive predictors, while BMI >30 kg/m2 was found to be a negative predictor for FCS. However, inclusion of additional FCS predictors had no significant impact on performance of standard FCS score. CONCLUSIONS: Our study validates the FCS score in the UK population to distinguish FCS from MCS. While additional FCS predictors were identified, they did not improve further the score diagnostic performance.

Breaking the chains of lipoprotein lipase deficiency: A pediatric perspective on the efficacy and safety of Volanesorsen.

RATIONALE: Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. METHODS: The patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. RESULTS: While the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. CONCLUSION: This study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.

Multifactorial chylomicronemia syndrome.

PURPOSE OF REVIEW: The aim of this review was to understand the role of multifactorial chylomicronemia syndrome (MFCS) as a cause of severe hypertriglyceridemia; to distinguish it from other causes of severe hypertriglyceridemia; and to provide a rational approach to treatment. RECENT FINDINGS: There have been advances in understanding the genetic underpinning of MFCS, and a better appreciation as to how to differentiate it from the much rarer familial chylomicronemia syndrome, in which there are substantial differences in the approach to their treatment. New approaches to triglyceride lowering will help reduce the risk of pancreatitis, the major complication of MFCS. SUMMARY: MCSF is a condition in which plasma triglyceride levels are severely elevated, usually to due exacerbation of common genetic forms of hypertriglyceridemia by secondary causes of hypertriglyceridemia and/or triglyceride-raising drugs. Triglyceride-induced pancreatitis can be prevented by markedly reducing triglyceride levels by treating secondary causes and/or eliminating of triglyceride-raising drugs, and by using triglyceride-lowering drugs, especially fibrates. MFCS also increases cardiovascular disease risk, for which lifestyle measures and drugs are required.

Genetic variation in apolipoprotein A-V in hypertriglyceridemia.

PURPOSE OF REVIEW: While biallelic rare APOA5 pathogenic loss-of-function (LOF) variants cause familial chylomicronemia syndrome, heterozygosity for such variants is associated with highly variable triglyceride phenotypes ranging from normal to severe hypertriglyceridemia, often in the same individual at different time points. Here we provide an updated overview of rare APOA5 variants in hypertriglyceridemia. RECENT FINDINGS: Currently, most variants in APOA5 that are considered to be pathogenic according to guidelines of the American College of Medical Genetics and Genomics are those resulting in premature termination codons. There are minimal high quality functional data on the impact of most rare APOA5 missense variants; many are considered as variants of unknown or uncertain significance. Furthermore, particular common polymorphisms of APOA5 , such as p.Ser19Trp and p.Gly185Cys in Caucasian and Asian populations, respectively, are statistically overrepresented in hypertriglyceridemia cohorts and are sometimes misattributed as being causal for chylomicronemia, when they are merely risk alleles for hypertriglyceridemia. SUMMARY: Both biallelic and monoallelic LOF variants in APOA5 are associated with severe hypertriglyceridemia, although the biochemical phenotype in the monoallelic state is highly variable and is often exacerbated by secondary factors. Currently, with few exceptions, the principal definitive mechanism for APOA5 pathogenicity is through premature truncation. The pathogenic mechanisms of most missense variants in APOA5 remain unclear and require additional functional experiments or family studies.

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This report presents a case of a male infant, aged 32 days, who was admitted to the hospital due to 2 days of bloody stools and 1 day of fever. Upon admission, venous blood samples were collected, which appeared pink. Blood biochemistry tests revealed elevated levels of triglycerides and total cholesterol. The familial whole genome sequencing revealed a compound heterozygous variation in the LPL gene, with one variation inherited from the father and the other from the mother. The patient was diagnosed with lipoprotein lipase deficiency-related hyperlipoproteinemia. Acute symptoms including bloody stools, fever, and bloody ascites led to the consideration of acute pancreatitis, and the treatment involved fasting, plasma exchange, and whole blood exchange. Following the definitive diagnosis based on the genetic results, the patient was given a low-fat diet and received treatment with fat-soluble vitamins and trace elements, as well as adjustments to the feeding plan. After a 4-week hospitalization, the patient's condition improved and he was discharged. Follow-up showed a decrease in triglycerides and total cholesterol levels. At the age of 1 year, the patient's growth and psychomotor development were normal. This article emphasizes the multidisciplinary diagnosis and treatment of familial hyperlipoproteinemia presenting with symptoms suggestive of acute pancreatitis, including bloody ascites, in the neonatal period.

Severe hypertriglyceridemia: Existing and emerging therapies.

Severe hypertriglyceridemia (sHTG), defined as a triglyceride (TG) concentration ≥ 500 mg/dL (≥ 5.7 mmol/L) is an important risk factor for acute pancreatitis. Although lifestyle, some medications, and certain conditions such as diabetes may lead to HTG, sHTG results from a combination of major and minor genetic defects in proteins that regulate TG lipolysis. Familial chylomicronemia syndrome (FCS) is a rare disorder caused by complete loss of function in lipoprotein lipase (LPL) or LPL activating proteins due to two homozygous recessive traits or compound heterozygous traits. Multifactorial chylomicronemia syndrome (MCS) and sHTG are due to the accumulation of rare heterozygous variants and polygenic defects that predispose individuals to sHTG phenotypes. Until recently, treatment of sHTG focused on lifestyle interventions, control of secondary factors, and nonselective pharmacotherapies that had modest TG-lowering efficacy and no corresponding reductions in atherosclerotic cardiovascular disease events. Genetic discoveries have allowed for the development of novel pathway-specific therapeutics targeting LPL modulating proteins. New targets directed towards inhibition of apolipoprotein C-III (apoC-III), angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), and fibroblast growth factor-21 (FGF21) offer far more efficacy in treating the various phenotypes of sHTG and opportunities to reduce the risk of acute pancreatitis and atherosclerotic cardiovascular disease events.

Variability of longitudinal triglyceride phenotype in patients heterozygous for pathogenic APOA5 variants.

BACKGROUND: Biallelic pathogenic variants in APOA5 are an infrequent cause of familial chylomicronemia syndrome characterized by severe, refractory hypertriglyceridemia (HTG), and fasting plasma triglyceride (TG) >10 mmol/L (>875 mg/dL). The TG phenotype of heterozygous individuals with one copy of a pathogenic APOA5 variant is less familiar. We evaluated the longitudinal TG phenotype of individuals with a single pathogenic APOA5 variant allele. METHODS: Medically stable outpatients from Ontario, Canada were selected for study based on having: 1) a rare pathogenic APOA5 variant in a single allele; and 2) at least three serial fasting TG measurements obtained over >1.5 years of follow-up. RESULTS: Seven patients were followed for a mean of 5.3 ± 3.7 years. Fasting TG levels varied widely both within and between patients. Three patients displayed at least one normal TG measurement (<2.0 mmol/L or <175 mg/dL). All patients displayed mild-to-moderate HTG (2 to 9.9 mmol/L or 175 to 875 mg/dL) at multiple time points. Five patients displayed at least one severe HTG measurement. 10%, 54%, and 36% of all TG measurements were in normal, mild-to-moderate, and severe HTG ranges, respectively. CONCLUSIONS: Heterozygosity for pathogenic variants in APOA5 is associated with highly variable TG phenotypes both within and between patients. Heterozygosity confers susceptibility to elevated TG levels, with secondary factors likely modulating the phenotypic severity.

Preclinical Development and Characterization of Novel Adeno-Associated Viral Vectors for the Treatment of Lipoprotein Lipase Deficiency.

Lipoprotein lipase deficiency (LPLD) results from mutations within the lipoprotein lipase (LPL) gene that lead to a complete lack of catalytically active LPL protein. Glybera was one of the first adeno-associated virus (AAV) gene replacement therapy to receive European Medicines Agency regulatory approval for the treatment of LPLD. However, Glybera is no longer marketed potentially due to a combination of economical, manufacturing, and vector-related issues. The aim of this study was to develop a more efficacious AAV gene therapy vector for LPLD. Following preclinical biodistribution, efficacy and non-Good Laboratory Practice toxicity studies with novel AAV1 and AAV8-based vectors in mice, we identified AAV8 pVR59. AAV8 pVR59 delivered a codon-optimized, human gain-of-function hLPLS447X transgene driven by a CAG promoter in an AAV8 capsid. AAV8 pVR59 was significantly more efficacious, at 10- to 100-fold lower doses, compared with an AAV1 vector based on Glybera, when delivered intramuscularly or intravenously, respectively, in mice with LPLD. Efficient gene transfer was observed within the injected skeletal muscle and liver following delivery of AAV8 pVR59, with long-term correction of LPLD phenotypes, including normalization of plasma triglycerides and lipid tolerance, for up to 6 months post-treatment. While intramuscular delivery of AAV8 pVR59 was well tolerated, intravenous administration augmented liver pathology. These results highlight the feasibility of developing a superior AAV vector for the treatment of LPLD and provide critical insight for initiating studies in larger animal models. The identification of an AAV gene therapy vector that is more efficacious at lower doses, when paired with recent advances in production and manufacturing technologies, will ultimately translate to increased safety and accessibility for patients.

Post-prandial analysis of fluctuations in the platelet count and platelet function in patients with the familial chylomicronemia syndrome.

BACKGROUND: The familial chylomicronemia syndrome (FCS) is an ultra rare disease caused by lipoprotein lipase (LPL) deficiency associated with potentially lethal acute pancreatitis risk. Thrombocytopenia (platelet count < 150,000 × 109/L) has been reported in patients with FCS, treated or not with volanesorsen, a second generation APOC3 anti-sense oligonucleotide. Chylomicrons are the lipoproteins delivering fat after a meal and FCS thus has a post-prandial origin. Platelet count and function have not been studied post-prandially in FCS. OBJECTIVE: To evaluate post-prandial fluctuations in the platelet count (PLC) and functional defects of hemostasis in FCS. METHODS: PLC, functional defects in hemostasis and hematologic variables were measured up-to 5 h after a meal in 6 homozygotes for FCS causing gene variants (HoLPL), 6 heterozygotes for LPL loss-of-function variants (HeLPL) and 7 normolipidemic controls. RESULTS: Hourly post-prandial PLC was significantly lower in HoLPL than in controls (P < 0.009). Compared to the other groups, the PLC tended to decrease rapidly (in the first hour) post-meal in HoLPL (P = 0.03) and remained lower than baseline 5-h post-meal (P = 0.02) whereas it tended to slightly increase in normolipidemic controls (P = 0.02). Platelet function was not affected by the prandial status. In HoLPL, post-prandial fluctuations in the PLC positively correlated with the lymphocyte count (P = 0.005) and negatively with neutrophil/lymphocyte ratio (NLR). CONCLUSION: The PLC decreases post-prandially in FCS (HoLPL), is not associated with changes in functional defects of hemostasis and correlates with the NLR, a marker of acute pancreatitis severity.

Volanesorsen and triglyceride levels in familial chylomicronemia syndrome: Long-term efficacy and safety data from patients in an open-label extension trial.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare, autosomal recessive genetic disorder characterized by a marked increase in plasma triglyceride (TG) levels and recurrent episodes of pancreatitis. The response to conventional TG-lowering therapies is suboptimal. Volanesorsen, an antisense oligonucleotide that targets hepatic apoC-III mRNA, has been shown to significantly reduce TGs in patients with FCS. OBJECTIVE: To further evaluate the safety and efficacy of extended treatment with volanesorsen in patients with FCS. METHODS: This phase 3 open-label extension study evaluated the efficacy and safety of extended treatment with volanesorsen in three groups of patients with FCS: Those who had previously received volanesorsen or placebo in the APPROACH and COMPASS studies, and treatment-naive patients not participating in either study. Key endpoints included change in fasting TG and other lipid measurements, and safety over 52 weeks. RESULTS: Volanesorsen treatment resulted in sustained reductions in plasma TG levels in previously treated patients from the APPROACH and COMPASS studies. Volanesorsen-treated patients from the three populations studied had mean decreases in fasting plasma TGs from index study baseline to months 3, 6, 12 and 24 as follows: decreases of 48%, 55%, 50%, and 50%, respectively (APPROACH); decreases of 65%, 43%, 42%, and 66%, respectively (COMPASS); and decreases of 60%, 51%, 47%, and 46%, respectively (treatment-naive). Common adverse events were injection site reactions and platelet count decrease, consistent with previous studies. CONCLUSION: Extended open-label treatment with volanesorsen in patients with FCS resulted in sustained reductions of plasma TG levels and safety consistent with the index studies.

Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial.

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg-1 or placebo every 4 weeks over a 12-week double-blind treatment period, followed by a 12-week single-blind treatment period. The primary end point was the mean percent reduction in triglycerides from baseline after 12 weeks of evinacumab exposure in cohort 3. Evinacumab reduced triglycerides in cohort 3 by a mean (s.e.m.) of -27.1% (37.4) (95% confidence interval -71.2 to 84.6), but the prespecified primary end point was not met. No notable differences in adverse events between evinacumab and placebo treatment groups were seen during the double-blind treatment period. Although the primary end point of a reduction in triglycerides did not meet the prespecified significance level, the observed safety and changes in lipid and lipoprotein levels support the further evaluation of evinacumab in larger trials of patients with sHTG. Trial registration number: ClinicalTrials.gov NCT03452228 .

Analyses of familial chylomicronemia syndrome in Pereira, Colombia 2010-2020: a cross-sectional study.

BACKGROUND AND AIM: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder caused by mutations in genes involved in chylomicron metabolism. On the other hand, multifactorial chylomicronemia syndrome (MCS) is a polygenic disorder and the most frequent cause of chylomicronemia, which results from the presence of multiple genetic variants related to chylomicron metabolism, in addition to secondary factors. Indeed, the genetic determinants that predispose to MCS are the presence of a heterozygous rare variant or an accumulation of several SNPs (oligo/polygenic). However, their clinical, paraclinical, and molecular features are not well established in our country. The objective of this study was to describe the development and results of a screening program for severe hypertriglyceridemia in Colombia. METHODS: A cross-sectional study was performed. All patients aged >18 years with triglyceride levels ≥500 mg/dL from 2010 to 2020 were included. The program was developed in three stages: 1. Review of electronic records and identification of suspected cases based on laboratory findings (triglyceride levels ≥500 mg/dL); 2. Identification of suspected cases based on laboratory findings that also allowed us to exclude secondary factors; 3. Patients with FCS scores <8 were excluded. The remaining patients underwent molecular analysis. RESULTS: In total, we categorized 2415 patients as suspected clinical cases with a mean age of 53 years, of which 68% corresponded to male patients. The mean triglyceride levels were 705.37 mg/dL (standard deviation [SD] 335.9 mg/dL). After applying the FCS score, 2.4% (n = 18) of patients met the probable case definition and underwent a molecular test. Additionally, 7 patients had unique variants in the APOA5 gene (c.694 T > C; p. Ser232Pro) or in the GPIHBP1 gene (c.523G > C; p. Gly175Arg), for an apparent prevalence of familial chylomicronemia in the consulting population of 0.41 per 1.000 patients with severe HTG measurement. No previously reported pathogenic variants were detected. CONCLUSION: This study describes a screening program for the detection of severe hypertriglyceridemia. Although we identified seven patients as carriers of a variant in the APOA5 gene, we diagnosed only one patient with FCS. We believe that more programs of these characteristics should be developed in our region, given the importance of early detection of this metabolic disorder.

Screening program for familial hyperchylomicronemia syndrome detection: Experience of a university health system.

Objective: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder caused by mutations related to chylomicron metabolism. The objective of this study is to show the development and results of a screening program for FCS in Argentina. Materials and methods: A cross-sectional study was performed. All patients > 18 years with a triglyceride level ≥ 1,000 mg/dL in the period from January 1, 2017 to December 31, 2021 were included. The program was developed in three stages: (1) Review of electronic records and identification of suspected laboratory cases (triglyceride level ≥ 1,000 mg/dL); (2) Identification of suspected clinical cases (all suspected laboratory cases that had no relevant secondary factors) and application of the FCS score to define probable cases (score ≥ 10); (3) Perform genetic tests in probable cases. Results: Globally, 348 suspected laboratory cases (mean age of 49.9 years, 77.3% men) were included. The median triglycerides level was 1,309 mg/dL (interquartile range 1,175-1,607 mg/dL). In total, 231 patients were categorized as suspected clinical cases. After applying the FCS score, 3% of them were classified as "very likely FCS" (probable cases). Four variants of uncertain significance have been identified. No previously reported pathogenic variants were detected. Conclusion: This study shows a screening program for the detection of FCS. Although no patient was diagnosed with FCS, we believe that more programs of these characteristics should be developed in our region, given the importance of early detection of this metabolic disorder.

Role of lipoprotein lipase activity measurement in the diagnosis of familial chylomicronemia syndrome.

BACKGROUND: Activity assays for lipoprotein lipase (LPL) are not standardised for use in clinical settings. OBJECTIVE: This study sought to define and validate a cut-off points based on a ROC curve for the diagnosis of patients with familial chylomicronemia syndrome (FCS). We also evaluated the role of LPL activity in a comprehensive FCS diagnostic workflow. METHODS: A derivation cohort (including an FCS group (n = 9), a multifactorial chylomicronemia syndrome (MCS) group (n = 11)), and an external validation cohort (including an FCS group (n = 5), a MCS group (n = 23) and a normo-triglyceridemic (NTG) group (n = 14)), were studied. FCS patients were previously diagnosed by the presence of biallelic pathogenic genetic variants in the LPL and GPIHBP1 genes. LPL activity was also measured. Clinical and anthropometric data were recorded, and serum lipids and lipoproteins were measured. Sensitivity, specificity and cut-offs for LPL activity were obtained from a ROC curve and externally validated. RESULTS: All post-heparin plasma LPL activity in the FCS patients were below 25.1 mU/mL, that was cut-off with best performance. There was no overlap in the LPL activity distributions between the FCS and MCS groups, conversely to the FCS and NTG groups. CONCLUSION: We conclude that, in addition to genetic testing, LPL activity in subjects with severe hypertriglyceridemia is a reliable criterium in the diagnosis of FCS when using a cut-off of 25.1 mU/mL (25% of the mean LPL activity in the validation MCS group). We do not recommend the NTG patient based cut-off values due to low sensitivity.

The advantages and pitfalls of genetic analysis in the diagnosis and management of lipid disorders.

The increasing affordability of and access to next-generation DNA sequencing has increased the feasibility of incorporating genetic analysis into the diagnostic pathway for dyslipidaemia. But should genetic diagnosis be used routinely? DNA testing for any medical condition has potential benefits and pitfalls. For dyslipidaemias, the overall balance of advantages versus drawbacks differs according to the main lipid disturbance. For instance, some patients with severely elevated low-density lipoprotein cholesterol levels have a monogenic disorder, namely heterozygous familial hypercholesterolaemia. In these patients, DNA diagnosis can be definitive, in turn yielding several benefits for patient care that tend to outweigh any potential disadvantages. In contrast, hypertriglyceridaemia is almost always a polygenic condition without a discrete monogenic basis, except for ultrarare monogenic familial chylomicronaemia syndrome. Genetic testing in patients with hypertriglyceridaemia is therefore predominantly non-definitive and evidence for benefit is presently lacking. Here we consider advantages and limitations of genetic testing in dyslipidaemias.