Familial Chylomicronemia Syndrome Patients Research Articles

A-222 Comparative Analysis of Clinical and Laboratory Parameters of Brazilian Patients with Severe Hipertriglyceridemia

Abstract Background The presence of elevated and sustained levels of triglycerides (TG) should raise the suspicion of primary causes of hypertriglyceridemia (HT), in which related genetic mutations would be identified. Thus, the aim of this study was to compare clinical and laboratory parameters of Brazilian patients with different etiologies of severe hypertriglyceridemia. Methods All patients with severe HT (considered as detection of TG above 880 mg/dL on at least 2 occasions) followed in the dyslipidemia outpatient clinic of Federal University of Ceará/Brazil, whose molecular study to investigate genetic variants potentially related to hypertriglyceridemia and pancreatitis has been previously performed (ABCA1 AGPAT2 AKT2 APOA5 APOC2 BSCL2 CAV1 CFTR CIDEC CTRC CYP27A1 GPIHBP1 LIPA LIPE LMF1 LMNA LMNB2 LPL PLIN1 POLD1 PPARG PRSS1 PSMB8 SMPD1 SPINK1 ZMPSTE24) were evaluated. Results Sixty-six patients were evaluated, identifying 39 (59%) with severe primary HT. Familial Chylomicronemia Syndrome (FCS) was identified in 14 (36%) of the 39 cases of severe primary HT. The main findings are shown in table 1. Compared with other etiologies, FCS patients presented an increased, precocious and recurrent incidence of pancreatitis, earlier detection and higher levels of TG. In patients with severe HT without identification of primary causes, a high incidence of alcoholism and diabetes was observed, with a tendency to higher glycated hemoglobin values among these, in addition to median Body Mass Index compatible with obesity. Conclusion FCS patients had the most severe clinical presentation of HT. The high prevalence of secondary factors for HT in patients with a negative genotype reinforces the indication of adequate management of these variables even in cases of primary etiology, aiming at not overlapping pathological mechanisms. In cases of severe HT, metabolic control is still a challenge.

Non-alcoholic fatty liver disease in patients with chylomicronemia syndromes

BackgroundChylomicronemia syndrome is a form of severe hypertriglyceridemia (HTG) caused by the familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS). Non-alcoholic fatty liver disease (NAFLD) has been associated with components of the metabolic syndrome and is more prevalent in subjects with elevated triglycerides. ObjectiveThe primary objective was to compare the prevalence of hepatic steatosis assessed by conventional imaging between HTG groups (FSC, MCS and moderate HTG (mHTG)). The secondary objective was to determine the difference in the prevalence of liver fibrosis. MethodsThis cross-sectional observational study was performed on adult patients from the lipid clinic of the Montreal Clinical Research Institute (IRCM). We retrospectively reviewed the imaging reports available in the patients’ files for signs of NAFLD. We also used the FIB-4 index as a surrogate marker of liver fibrosis. ResultsWe reviewed the medical files of 300 patients; 22 with FCS, 82 with MCS and 196 with mHTG. There was significantly more hepatic steatosis in the MCS group compared to the mHTG and FCS groups (79%, 66% and 43% respectively p=0.02). There was a significantly higher prevalence of subjects within the “unlikely fibrosis” category in the mHTG group (91%) compared to the MCS (84%) and FCS groups (59%), p=0.0004. ConclusionWe found that the prevalence of hepatic steatosis was 3-, 2.5-, and 2-fold higher in MCS, mHTG and FCS patients than in the general population. This suggests that patients with elevated triglycerides, regardless of the underlying etiology, are at higher risk of hepatic steatosis and NAFLD.

Thrombocytopenia and Kidney disease, two possible hallmark of FCS phenotype: preliminary evidence from a cohort study

Background and Aim: Familial Chylomicronemia Syndrome (FCS) is a rare monogenic autosomal recessive disorder of lipid metabolism determining severe hypertriglyceridemia (HTG). As the use of Volanesorsen, a novel FCS treating drug, has been associated with thrombocytopenia, the relationship between FCS and low platelets counts should be firmly established. It has been reported also kidney complication in FCS, but the data are sparse. To this aim, we have retrospectively evaluated the spontaneous variation of platelet counts and Kidney impairment in a cohort of patients with FCS. Methods: Single-center retrospective cohort study on 20 FCS patients included in the LIPIGEN. Medical charts have been revised to collect retrospectively information on kidney function in a cohort of patients with FCS. Results: Across the study population, the median PLT count was 187,225 platelet/mcL. The median on treatment TG levels in the whole cohort was 1309 mg/dl. During follow-up, 8 (44.4%) patients experienced at least one episode of mild and 1 (5%) of moderate thrombocytopenia. None had severe thrombocytopenia. Mean triglycerides do not significantly predict mean platelet values. However, when considering a multivariate model including mean triglycerides, sex, the presence of hepatic steatosis and age we found that male sex and the presence of ultrasound estimated hepatic steatosis were associated with significantly lower platelet (respectively β-0,473, P=0,044 and β-0,469, P=0,048). Age was of borderline statistical significance (β-0,388, P=0,087). Across the study population, the median GFR values was 99.5 ml/min. Median eGFR was significantly associated with history of hypertension (β-0,508, P=0,031). Overall, proteinuria occurred in 5 (25%) patients, and it did not associate with hypertension, diabetes, age, sex nor triglyceride levels. Four (20.0%) patients meet the criteria of hyperfiltration whereas 3 (15.0%) were exhibiting an eGFR below 90 ml/min. Among hyperfiltrating, two had also proteinuria in at least one occasion during life. One patient with eGFR below 90 ml/min and proteinuria had a biopsy-proven diagnosis of glomerulonephritis. Overall, the impairment in kidney function was independent from age, diabetes, hypertension, median TGs, AP, sex. Conclusions: The present analysis confirmed that thrombocytopenia and kidney impairment might be a clinical characteristics of FCS phenotype. Further studies in larger cohort are needed to better clarify if kidney disease and thrombocytopenia might be a hallmark of FCS in broader population and understand the potential patho-physiological mechanism.

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

Activity assays for lipoprotein lipase (LPL) are not standardised for use in clinical settings. 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. 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. 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. 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.

Identifying Patients with Familial Chylomicronemia Syndrome Using FCS Score-Based Data Mining Methods.

Background: There are no exact data about the prevalence of familial chylomicronemia syndrome (FCS) in Central Europe. We aimed to identify FCS patients using either the FCS score proposed by Moulin et al. or with data mining, and assessed the diagnostic applicability of the FCS score. Methods: Analyzing medical records of 1,342,124 patients, the FCS score of each patient was calculated. Based on the data of previously diagnosed FCS patients, we trained machine learning models to identify other features that may improve FCS score calculation. Results: We identified 26 patients with an FCS score of ≥10. From the trained models, boosting tree models and support vector machines performed the best for patient recognition with overall AUC above 0.95, while artificial neural networks accomplished above 0.8, indicating less efficacy. We identified laboratory features that can be considered as additions to the FCS score calculation. Conclusions: The estimated prevalence of FCS was 19.4 per million in our region, which exceeds the prevalence data of other European countries. Analysis of larger regional and country-wide data might increase the number of FCS cases. Although FCS score is an excellent tool in identifying potential FCS patients, consideration of some other features may improve its accuracy.

Safety and efficacy of therapies for chylomicronemia

Introduction Primary chylomicronemia is characterized by pathological accumulation of chylomicrons in plasma causing severe hypertriglyceridemia, typically >10 mmol/L (>875 mg/dL). Patients with the ultra-rare familial chylomicronemia syndrome (FCS) subtype completely lack lipolytic capacity and respond minimally to traditional triglyceride-lowering therapies. The mainstay of treatment is a low-fat diet, which is difficult to follow and compromises quality of life. New therapies are being developed primarily to prevent episodes of life-threatening acute pancreatitis. Areas covered Antagonists of apolipoprotein (apo) C-III, such as the antisense oligonucleotide (ASO) volanesorsen, significantly reduce triglyceride levels in chylomicronemia. However, approval of and access to volanesorsen are restricted since a substantial proportion of treated FCS patients developed thrombocytopenia. Newer apo C-III antagonists, namely the ASO olezarsen (formerly AKCEA-APOCIII-LRx) and short interfering RNA (siRNA) ARO-APOC3 appear to show efficacy with less risk of thrombocytopenia. Potential utility of antagonists of angiopoietin-like protein 3 (ANGPTL3) such as evinacumab and the siRNA ARO-ANG3 in subtypes of chylomicronemia remains to be defined. Expert opinion Emerging pharmacologic therapies for chylomicronemia show promise, particularly apo C-III antagonists. However, these treatments are still investigational. Further study of their efficacy and safety in patients with both rare FCS and more common multifactorial chylomicronemia is needed.

Volanesorsen: A New Era in the Treatment of Severe Hypertriglyceridemia.

Introduction: Familial chylomicronemia syndrome (FCS) is a rare inherited disease, mainly due to lipoprotein lipase (LPL) gene mutations, leading to lipid abnormalities. Volanesorsen, a second-generation 2′-O-methoxyethyl (2′-MOE) chimeric antisense therapeutic oligonucleotide, can decrease plasma apolipoprotein C3 and triglycerides (TG) levels through LPL-independent pathways. The European Medicines Agency has approved volanesorsen as an adjunct to diet in adult FCS patients with an inadequate response to TG-lowering therapy. Areas covered: Available clinical data on volanesorsen efficacy and safety are presented. Furthermore, we discuss the yearly treatment with volanesorsen of a 21-year-old female FCS patient with LPL mutation. Volanesorsen was well-tolerated and decreased patient’s TG levels (from >5000 mg/dL (56 mmol/L) to 350–500 mg/dL (4–5.6 mmol/L)) at 12 months. Lipoprotein apheresis (LA) was stopped and there were no episodes of pancreatitis or abdominal pain. Expert opinion: Severe hypertriglyceridemia can potentially be fatal. Until recently, there was no specific treatment for FCS, apart from hypotriglyceridemic diet, fibrates, omega-3 fatty acids, and LA sessions. Therefore, volanesorsen represents a promising therapeutic solution for these patients. The main side effect of volanesorsen therapy is thrombocytopenia, which should be monitored and treated accordingly. Increasing evidence will further elucidate the clinical implications of volanesorsen use in daily practice.

Volanesorsen for treatment of familial chylomicronemia syndrome

ABSTRACT Introduction Familial chylomicronemia syndrome (FCS) is a rare subtype of severe hypertriglyceridemia that affects ~1 in 100, 000 to 1,000,000 individuals. The major risk to health is acute pancreatitis. FCS is defined by biallelic loss-of-function mutations in one of five canonical genes that encode proteins critical to lipolysis of large triglyceride-rich lipoprotein particles. Unlike the vast majority of patients with severe hypertriglyceridemia, FCS patients lack any lipolytic capacity and are thus resistant to standard medications. Areas covered This review focuses on a mechanism that effectively reduces elevated triglyceride levels in FCS, namely interference of synthesis of apolipoprotein (apo) C-III. Volanesorsen is an antisense RNA drug administered subcutaneously that knocks down apo C-III, resulting in dramatic reductions in triglyceride levels both in FCS patients and in the wider population of subjects with severe hypertriglyceridemia. Expert opinion Volanesorsen is a highly effective treatment to reduce elevated triglycerides in FCS patients, providing proof-of-concept of the validity of targeting apo C-III. However, off target effects of volanesorsen, including thrombocytopenia, may ultimately limit its use. Nonetheless, building on the knowledge derived from the volanesorsen experience, there is intensified interest in promising newer agents that also target apo C-III but have technical modifications that limit potential off target adverse effects.

10-Year Comparative Follow-up of Familial versus Multifactorial Chylomicronemia Syndromes.

The relative incidence of acute pancreatitis, ischemic cardiovascular disease, and diabetes in hyperchylomicronemic patients exhibiting familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) is unknown. The objective was to study the occurrence of these events in FCS and MCS patients compared with the general population. Twenty-nine FCS and 124 MCS patients, with genetic diagnosis, in 4 lipid clinics were matched with 413 controls. Individual hospital data linked to the national claims database were collected between 2006 and 2016. The occurrence of complications was retrospectively assessed before follow-up and during a median follow-up time of 9.8 years, for 1500 patient years of follow-up. Patients with FCS were younger than those with MCS (34.3 ± 13.6 vs 45.2 ± 12.6 years, P < 0.01). During the study period, 58.6% of the FCS patients versus 19.4% of the MCS patients had at least 1 episode of acute hypertriglyceridemic pancreatitis (AHP) (hazard ratio [HR] = 3.6; P < 0.01). Conversely, the ischemic risk was lower in FCS than in MCS (HR = 0.3; P = 0.05). The risk of venous thrombosis was similar in both groups. The incidence of diabetes was high in both groups compared with matched controls (odds ratio [OR] = 22.8; P < 0.01 in FCS and OR = 30.3; P < 0.01 in MCS). The incidence of AHP was much higher in FCS than in MCS patients, whereas the incidence of ischemic cardiovascular events was found to be increased in MCS versus FCS patients and a representative matched control group. Differences in both triglyceride-rich lipoproteins metabolism and comorbidities in MCS versus FCS drive the occurrence of different patterns of complications.

Involvement of a homozygous exon 6 deletion of LMF1 gene in intermittent severe hypertriglyceridemia

Severe hypertriglyceridemia (HTG), characterized by triglycerides (TG) permanently over 10 mmol/L, may correspond to familial chylomicronemia syndrome (FCS), a rare disorder. However, hypertriglyceridemic patients more often present multifactorial chylomicronemia syndrome (MCS), characterized by highly variable TG. A few nonsense variants of LMF1 gene were reported in literature in FCS patients. In this study, we described a woman with an intermittent severe HTG. NGS analysis and the sequencing of a long range PCR product revealed a homozygous deletion of 6507 base pairs in LMF1 gene, c.730-1528_898-3417del, removing exon 6, predicted to create an in-frame deletion of 56 amino acids, p.(Thr244_Gln299del). Despite an exon 6 homozygous deletion of LMF1, the patient’s highly variable lipid phenotype was suggestive of MCS diagnosis.

Familial Chylomicronemia Syndrome (FCS): Recent Data on Diagnosis and Treatment.

Familial chylomicronemia syndrome (FCS) is a rare recessive genetic disorder often underdiagnosed with potentially severe clinical consequences. In this review, we describe the clinical and biological characteristics of the disease together with its main complication, i.e., acute pancreatitis. We focused the paper on new diagnostic tools, progress in understanding the role of two key proteins (apolipoprotein CIII (apo CIII) and angiopoietin-like3 (ANGPTL-3)), and new therapeutic options. Recently, a new diagnostic tool has been proposed by European experts to help identify these patients. This tool with two recently identified parameters (low LDL and low body mass index) can help identify patients who should be genetically tested or who may have the disease when genetic testing is not available. FCS is caused by homozygous or compound heterozygous mutations of lipoprotein lipase, apolipoprotein C-II, apolipoprotein A-V, glycosylphosphatidylinositol anchored high-density lipoprotein-binding protein 1, and lipase maturation factor. Two proteins have been identified as important player in the metabolism of triglyceride-rich lipoprotein and its regulation. These two proteins are therapeutic target. Antisense oligonucleotide targeting apo CIII has been shown to significantly decrease triglyceride levels even in FCS and is the first available treatment for these patients. Further development might identify new compounds with reduced risk to develop severe thrombocytopenia. ANGPTL-3 inhibitors have not yet been tested in FCS patients but exert significant hypotriglyceridemic effect in the more frequent and less severe polygenic forms. Beyond these two new targets, microsomal triglyceride transfer protein (MTTP) inhibitors could also be part of the armamentarium, if on-going trials confirm their efficacy. New clinical tools and simple criteria can help select patients with possible FCS and identify patients who should have a genetic testing. Identifying patients with FCS is a major issue since these patients have a high risk to suffer severe episodes of acute pancreatitis and may now benefit from new therapeutic options including antisense oligonucleotide targeting apo CIII.

Analysis of a Chinese Pedigree With Familial Chylomicronemia Syndrome Reveals Two Novel LPL Mutations by Whole-Exome Sequencing

Familial chylomicronemia syndrome (FCS) is a rare monogenic autosomal recessive disease caused by loss-of-function mutations in genes involved in chylomicron breakdown through hydrolysis of triglycerides into free fatty acids. Patients are often diagnosed in early childhood with extremely high triglyceride levels and symptoms including abdominal pain, eruptive cutaneous xanthomata, hepatosplenomegaly, and significant cognitive, psychological, and social impairment. The most serious medical condition suffered by FCS patients is recurrent acute pancreatitis. Lipoprotein lipase (LPL) gene mutation accounts for majority of the known pathogenic mutations. Early diagnosis and strict low-fat diet are critical for successful management of the triglyceride concentration to lower the risk of pancreatitis. The true prevalence of FCS in China is unknown and here we report a Chinese female preterm neonate presented with an extremely high triglyceride level of 22.11 mmol/L on day 13 after birth. Clinical and laboratory workup including whole-exome sequencing revealed two novel compound heterozygous LPL mutations (c.406G > C and c.829G > C) that are co-segregated with her non-consanguineous parents, consistent with autosomal recessive inheritance. A diagnosis of FCS based on clinical, biochemical, and genetic ground was made to guide her management.

Familial chylomicronemia syndrome: an under-recognized cause of severe hypertriglyceridaemia.

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder of chylomicron metabolism causing severe elevation of triglyceride (TG) levels (>10mmolL-1 ). This condition is associated with a significant risk of recurrent acute pancreatitis (AP). AP caused by hypertriglyceridaemia (HTG) has been associated with a worse prognosis and higher mortality rates compared to pancreatitis of other aetiology. Despite its association with poor quality of life and increased lifelong risk of HTG-AP, few healthcare providers are familiar with FCS. Because this condition is under-recognized, the majority of FCS patients are diagnosed after age 20 often after consulting several physicians. Although other forms of severe HTG such as multifactorial chylomicronemia have been associated with high atherosclerotic cardiovascular disease (ASCVD) risk and metabolic abnormalities, ASCVD and metabolic syndrome are not usually observed in FCS patients. Because FCS is a genetic condition, the optimal diagnosis strategy remains genetic testing. The presence of bi-allelic pathogenic mutations in LPL, APOC2, GPIHBP1, APOA5 or LMF1 genes confirms the diagnosis. However, some cases of FCS caused by autoantibodies against LPL or GPIHBP1 proteins have also been reported. Furthermore, a clinical score for the diagnosis of FCS has been proposed but needs further validation. Available treatment options to lower triglycerides such as fibrates or omega-3 fatty acids are not efficacious in FCS patients. Currently, the cornerstone of treatment remains a lifelong very low-fat diet, which prevents the formation of chylomicrons. Finally, inhibitors of apo C-III and ANGPTL3 are in development and may eventually constitute additional treatment options for FCS patients.

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

Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are the prototypes of monogenic and polygenic conditions underlying genetically based severe hypertriglyceridemia. These conditions have been only partially investigated so that a systematic comparison of their characteristics remains incomplete. We aim to compare genetic profiles and clinical outcomes in FCS and MCS. Approach and Results: Thirty-two patients with severe hypertriglyceridemia (triglyceride >1000 mg/dL despite lipid-lowering treatments with or without history of acute pancreatitis) were enrolled. Rare and common variants were screened using a panel of 18 triglyceride-raising genes, including the canonical LPL, APOC2, APOA5, GP1HBP1, and LMF1. Clinical information was collected retrospectively for a median period of 44 months. Across the study population, 37.5% were classified as FCS due to the presence of biallelic, rare mutations and 59.4% as MCS due to homozygosity for nonpathogenic or heterozygosity for pathogenic variants in canonical genes, as well as for rare and low frequency variants in noncanonical genes. As compared with MCS, FCS patients showed a lower age of hypertriglyceridemia onset, higher levels of on-treatment triglycerides, and 3-fold higher incidence rate of acute pancreatitis. Our data indicate that the genetic architecture and natural history of FCS and MCS are different. FCS expressed the most severe clinical phenotype as determined by resistance to triglyceride-lowering medications and higher incidence of acute pancreatitis episodes. The most common genetic abnormality underlying FCS was represented by biallelic mutations in LPL while APOA5 variants, in combination with high rare polygenic burden, were the most frequent genotype of MCS.

Chylomicronemia: Differences between familial chylomicronemia syndrome and multifactorial chylomicronemia

Background and aimsChylomicronemia can be either monogenic or multifactorial. The monogenic form, namely familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease that strongly predisposes to pancreatitis. However, the clinical variables differentiating FCS from multifactorial chylomicronemia (MCM) are not well established. The aims of the present study were to describe a well-defined cohort of FCS subjects and to investigate the differences between patients with FCS and MCM. MethodsA total of 25 FCS and 36 MCM patients were included in the present study. FCS patients were genetically confirmed, whereas MCM patients had negative genetic testing, triglycerides above 10 mmol/L at least once and the presence of both chylomicrons and VLDL in plasma. ResultsFCS patients presented a significant higher frequency of pancreatitis (60% vs. 6%), multiple pancreatitis (48% vs. 3%) and abdominal pain (63% vs. 19%) and a lower frequency of metabolic abnormalities than in the MCM group (p < 0.0001). In addition, the frequency of cardiovascular events was higher in the MCM group than in the FCS group (17% vs. 0%), although the difference was not statistically significant (p = 0.07). In a univariate regression model, the significant predictors of FCS were age at first manifestation (β = −2.11, p = 0.0005), body mass index (BMI) (β = −1.82, p < 0.001) and gamma-glutamyl transferase (GGT) (β = −1.64, p = 0.001). ConclusionsOur study identified several variables that significantly differentiates FCS from MCM patients. These results need to be replicated in larger cohorts to identify the independent predictors of FCS.

Assessing the disease burden among patients with familial chylomicronemia syndrome (FCS) on volanesorsen: Results of the re-focus study

Aim: To evaluate the potential impact of volanesorsen treatment on the burden of illness (BoI) for FCS patients.

Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study

Familial chylomicronemia syndrome (FCS) is a rare metabolic disorder caused by mutations in lipoprotein lipase (LPL) or genes required for LPL functionality and is characterized by hyperchylomicronemia that results in recurrent episodes of acute pancreatitis. Owing to the rarity of FCS, there are few case series describing the phenotypic variability in FCS patients in detail. To provide baseline characteristics in the largest study population to date of patients with FCS. We analyzed baseline demographic and clinical characteristics of adult FCS patients in the phase 3 APPROACH study of volanesorsen sodium (antisense inhibitor of apolipoprotein C-III). Sixty-six patients were included in the analysis. Mean (SD) age was 46 (13) years; and mean body mass index was 24.9 (5.7) kg/m2. We identified causal mutations in 79% (52) of patients, with LPL mutations accounting for 62% (41) of cases. Median age at diagnosis was 24years, 54% were females, and 81% were Caucasian. All patients followed a low-fat diet, 43% received fibrates, 27% fish oils, and 21% statins. Median fasting triglyceride levels (P25, P75) were 1985 (1179, 3047mg/dL). Overall, 76% of patients reported ≥1 lifetime episode of acute pancreatitis; 23 patients reported a total of 53 pancreatitis events in the 5years before enrollment. Our data emphasize the severe hypertriglyceridemia characteristic of FCS patients despite restrictive low-fat diets and frequent use of existing hypolipemic therapies. Acute pancreatitis and recurrent acute pancreatitis are frequent complications of FCS. Diagnosis at an older age suggests likely underdiagnosis and underappreciation of this rare disorder.

Clinical and biochemical features of different molecular etiologies of familial chylomicronemia

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. We evaluated baseline phenotypes among FCS participants in a phase 3 randomized placebo-controlled trial of volanesorsen (NCT02211209). Baseline clinical, fasting, and postfat load metabolic markers were assessed. Targeted next-generation DNA sequencing plus custom bioinformatics was used to genotype subjects. 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. 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.

The burden of familial chylomicronemia syndrome from the patients’ perspective

ABSTRACTBackground: Familial chylomicronemia syndrome (FCS) is a rare, inherited lipid disorder characterized by high levels of plasma triglycerides and chylomicrons, which may cause life-threatening acute pancreatitis. Currently no FDA-approved treatment exists. Management is low-fat diet (<20g fat/day), which is difficult to maintain. With the restricted diet, triglycerides may remain elevated. We conducted discussions with patients and caregivers to better understand the burden of FCS from their perspectives.Methods: A panel of FCS patients and caregivers was assembled to discuss and assess the clinical and psychosocial burden of FCS.Results: Ten adults with FCS (median age 48 yr) and their spouses/caregivers were asked specific questions about their experiences living with FCS. Patients with FCS stated their symptoms were abdominal pain, nausea, diarrhea, constipation, bloating, and fatigue. Patients reported a median of 34 episodes of acute pancreatitis over their lifetimes; half of these led to hospitalizations, each with an average stay of 6.5 days. The psychosocial burden of FCS was primarily associated with the restricted diet, anxiety and stress of FCS.Conclusions: Living with FCS imposes a significant clinical and psychosocial burden on patients and caregivers, who reported reduced quality of life, limited employment opportunities, socialization and increased burden on family.

The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study

ABSTRACTBackground: Familial Chylomicronemia Syndrome (FCS) is a rare genetic disorder that is caused by a decrease or an absence of lipoprotein lipase activity. FCS is characterized by marked accumulation of chylomicrons and extreme hypertriglyceridemia, which have major effects on both physical and mental health. To date, there have been no systematic efforts to characterize the impact of chylomicronemia on FCS patients’ lives. In particular, the impact of FCS on the burden of illness (BoI) and quality of life (QoL) has not been fully described in the literature.Methods: IN-FOCUS was a comprehensive web-based research survey of patients with FCS focused on capturing the BoI and impact on QoL associated with FCS. Sixty patients from the US diagnosed with FCS participated. Patients described multiple symptoms spanning across physical, emotional and cognitive domains.Results: Patients on average cycled through 5 physicians of varying specialty before being diagnosed with FCS, reflecting a lengthy journey to diagnosis Nearly all respondents indicated that FCS had a major impact on BoI and QoL and significantly influenced their career choice and employment status, and caused significant work loss due to their disease.Conclusion: FCS imparts a considerable burden across multiple domains with reported impairment on activities of daily living and QoL.