Familial Chylomicronemia Research Articles

Molecular basis of the familial chylomicronemia syndrome in patients from the national dyslipidemia registry of the Spanish atherosclerosis society

Molecular basis of the familial chylomicronemia syndrome in patients from the national dyslipidemia registry of the Spanish atherosclerosis society

Lipaemia retinalis in familial chylomicronaemia syndrome

Lipaemia retinalis in familial chylomicronaemia syndrome

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

Aim: on the Behalf of the FCS diagnosis task force

The effect of volanesorsen treatment on the burden associated with familial chylomicronemia syndrome: the results of the ReFOCUS study

ABSTRACTBackground: Volanesorsen, an investigational inhibitor of apoC-III synthesis, significantly reduced triglyceride levels in clinical trials in patients with familial chylomicronemia syndrome (FCS), a rare genetic disorder characterized by marked chylomicronemia leading to a spectrum of symptoms, including recurrent abdominal pain and episodes of potentially fatal acute pancreatitis (AP).Objective: To determine the effect of volanesorsen on burden of disease on patients with FCSMethods: ReFOCUS was a retrospective global web-based survey open to patients with FCS who received volanesorsen for ≥3 months in an open-label extension study. The survey included questions about patients’ experiences before and after volanesorsen treatment.Results: Twenty-two respondents had received volanesorsen for a median of 222 days. Volanesorsen significantly reduced the number of symptoms per patient across physical, emotional, and cognitive domains. Significant reductions from baseline were reported for steatorrhea, pancreatic pain, and constant worry about an attack of pain/AP. Respondents reported that volanesorsen improved overall management of symptoms and reduced interference of FCS with work/school responsibilities. Reductions in the negative impact of FCS on personal, social, and professional life were also reported.Conclusions: Treatment with volanesorsen has the potential to reduce disease burden in patients with FCS through modulation of multiple symptom domains.

Disappearance of recurrent pancreatitis after splenectomy in familial chylomicronemia syndrome

Background and aimsRecurrent pancreatitis is a severe complication of familial chylomicronemia syndrome (FCS) mainly secondary to lipoprotein lipase deficiency. The mechanism and interindividual variability of pancreatitis in FCS are not fully understood, but abnormalities in the drainage system of pancreatic veins could be involved. Methods and resultsTwo cases of typical FCS are described with a past history of recurrent pancreatitis that dramatically improved after splenectomy performed in both cases for reasons non-related to FCS. ConclusionsThese are the first reports of the disappearance of pancreatitis after splenectomy in FCS and they should be considered of anecdotal nature at this time. The disappearance of pancreatitis following splenectomy could be in part due to subsequent improvements in pancreatic drainage. Extrahepatic portal hypertension induced by hypertriglyceridemic splenomegaly leading to pancreatic congestion could also be a contributing factor.

Assessing the Burden of Illness and Impact on Quality of Life in Patients with Familial Chylomicronemia Syndrome: Canadian Cohort Analysis

Assessing the Burden of Illness and Impact on Quality of Life in Patients with Familial Chylomicronemia Syndrome: Canadian Cohort Analysis

Treatment with volanesorsen (VLN) reduced triglycerides and pancreatitis in patients with familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (sHTG) vs placebo: Results of the approach and compass studies

Volanesorsen is an antisense oligonucleotide that targets hepatic apolipoprotein C-III synthesis and reduces plasma triglyceride concentration. The aim of this study was to explore the safety and efficacy of volanesorsen in patients with multifactorial chylomicronaemia syndrome.The COMPASS trial was a randomised, placebo-controlled, double-blind, phase 3 study done at 38 international clinical sites in Canada, France, Germany, the Netherlands, UK, and USA. Eligible patients were aged 18 years or older with multifactorial severe hypertriglyceridaemia or familial chylomicronaemia syndrome, who had a BMI of 45 kg/m2 or less and fasting plasma triglyceride of 500 mg/dL or higher. Patients were randomly assigned (2:1) with an interactive response system using an allocation sequence and permuted block randomisation to receive subcutaneous volanesorsen (300 mg) or a matched volume of placebo (1·5 mL) once a week for 26 weeks. After 13 weeks of treatment, dosing was changed to 300 mg of volanesorsen or placebo every 2 weeks for all patients, except those who had completed 5 months or more of treatment as of May 27, 2016. Participants, investigators, sponsor personnel, and clinical research staff were all masked to the treatment assignments. The primary outcome was percentage change from baseline to 3 months in fasting triglyceride in the full analysis set (all patients who were randomly assigned and received at least one dose of study drug and had a baseline fasting triglyceride assessment). This trial is registered with ClinicalTrials.gov, NCT02300233 (completed).Between Feb 5, 2015, and Jan 24, 2017, 408 patients were screened for eligibility. 294 were excluded and 114 randomly assigned to receive either volanesorsen (n=76) or placebo (n=38). One patient in the volanesorsen group discontinued before receiving the study drug. The total number of dropouts was 28 (four in the placebo group and 24 in the treatment group). Volanesorsen reduced mean plasma triglyceride concentration by 71·2% (95% CI −79·3 to −63·2) from baseline to 3 months compared with 0·9% (−13·9 to 12·2) in the placebo group (p<0·0001), representing a mean absolute reduction of fasting plasma triglycerides of 869 mg/dL (95% CI −1018 to −720; 9·82 mmol/L [–11·51 to −8·14]) in volanesorsen compared with an increase in placebo of 74 mg/dL (−138 to 285; 0·83 mmol/L [–1·56 to 3·22]; p<0·0001). In the key safety analysis, five adjudicated events of acute pancreatitis occurred during the study treatment period, all in three of 38 patients in the placebo group. The most common adverse events were related to tolerability and included injection-site reactions (average of 24% of all volanesorsen injections vs 0·2% of placebo injections), which were all mild or moderate. One participant in the volanesorsen group had a platelet count reduction to less than 50 000 per μL and one patient had serum sickness, both of which were regarded as serious adverse events.Volanesorsen significantly reduced triglyceride concentrations in patients with multifactorial chlyomicronaemia and might reduce acute pancreatitis events in these patients.Ionis Pharmaceuticals and Akcea Therapeutics.

Familial Chylomicronemia Syndrome: Description of a French Canadian Cohort

Quantitative sensory testing (QST) has been previously used to study pain in chronic pancreatitis (CP) but included methods that are not suitable for clinical purposes. The aims of this study were to determine if pancreatic QST (P-QST) can differentiate patients into distinct pain phenotypes and to determine the association of these with their clinical pain and psychiatric comorbidities.A multicenter cross-sectional study was conducted where patients completed validated questionnaires assessing quality of life (QoL), depression and anxiety scores as well as clinical pain symptoms followed by P-QST which included a cold pressor test, repetitive pinprick stimuli and pressure stimulation of the upper abdominal (T10) and control dermatomes. P-QST categorized patients into pain phenotypes based on a previously established nomogram. QoL, clinical pain and psychiatric assessment scores were compared across these groups.A total of 179 patients were enrolled with a mean age of 54.1±13.6 years among whom 59% were males and 42% had an alcoholic etiology. P-QST showed no hyperalgesia in 91 (51%), segmental hyperalgesia in 50 (28%) and widespread hyperalgesia in 38 (21%) patients. Patients with widespread hyperalgesia had significantly higher pain intensity scores (P = .03) and rates of constant pain (P = .002) as well as decreased QoL (P < .001) and physical functioning (P =.03) in comparison with the other two pain phenotypes. In contrast, psychiatric comorbidities were similar across all groups.P-QST may serve as a novel unbiased pain assessment tool in CP as it categorizes patients into distinct pain phenotypes independent of their psychiatric comorbidities.

Examining the High Disease Burden and Impact on Quality of Life in Familial Chylomicronemia Syndrome

Examining the High Disease Burden and Impact on Quality of Life in Familial Chylomicronemia Syndrome

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.

Identifying suspected familial chylomicronemia syndrome

ABSTRACTFamilial chylomicronemia syndrome (FCS) is a rare lipid disorder posing significant clinical burdens on patients. Due to its rarity, variety of presentations, and lack of universal diagnostic criteria, patients see an average of five physicians before diagnosis. We screened adults for a triglyceride level ≥1000 mg/dL from September 2015 to September 2016 and a history of pancreatitis and performed a thorough chart review on those who met the criteria. An adjudication panel used a definition that also called for supportive information including history of hypertriglyceridemia or family history of pancreatitis/hypertriglyceridemia. Among 297,891 adults with laboratory values available, 334 (0.11%) had triglyceride levels ≥1000 mg/dL, and 30 (9%) of those had pancreatitis. Most of these 30 patients were male (73%), had diabetes (90%), were taking a fibrate (93%), and were taking a statin (80%). The average body mass index was 32.5 ± 4.5 kg/m2. Six cases were ruled out, primarily due to substance abuse and/or isolated pancreatitis. Of the 24 suspected FCS cases, the average maximum triglyceride level was 3085 ± 1211 mg/dL. Electronic screening methods based solely on triglycerides ≥1000 mg/dL and pancreatitis eliminated 99.99% of the population, enabling the adjudication panel to focus on 30 cases. In 24 cases, FCS could not be ruled out; hence, the prevalence of FCS may be as high as 1 in 12,413.

Familial chylomicronemia syndrome: Bringing to life dietary recommendations throughout the life span

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder with loss of function mutations of lipoprotein lipase resulting in hypertriglyceridemia and accumulation of chylomicrons in plasma, often leading to acute pancreatitis. The mainstay of treatment is a specialized very-low-fat diet. Even adhering to the diet, some patients may experience high triglycerides and pancreatitis. There currently are no comprehensive dietary guidelines. To report best practices and develop comprehensive dietary guidelines for nutrition therapy in patients with FCS. Registered dietitian nutritionists (RDNs) convened to develop this report based on experience treating patients with FCS and a review of current literature on the topic. One author provided a patient perspective of living with FCS. This report provides guidelines and rationales for nutrition therapy associated with FCS across the life span. The top global guidelines are to (1) limit fat to <15 to 20g per day (<10%-15% of total daily energy intake); (2) meet recommendations for essential fatty acids: α-linolenic acid and linoleic acid; (3) choose complex carbohydrate foods while limiting simple and refined carbohydrate foods; (4) supplement with fat-soluble vitamins, minerals, and medium-chain triglyceride oil, as needed; (5) adjust calories for weight management. Recommended foods include vegetables, whole grains, legumes, lean protein foods, fruits in limited amounts, and fat-free milk products without added sugars. Foods to avoid include alcohol and products high in sugar. These patient-centered nutrition guidelines provide guidance to help patients adhere to the recommended diet and optimize nutritional needs.

The burden of familial chylomicronemia syndrome: Results from the global IN-FOCUS study

Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by a deficiency of lipoprotein lipase leading to extreme hypertriglyceridemia. Patients' burden of illness and quality of life have been poorly addressed in the literature. To understand the ways in which FCS impacts patients' lives. Investigation of Findings and Observations Captured in Burden of Illness Survey (IN-FOCUS) was a global web-based survey open to patients with FCS. Survey questions captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions. Of 166 patients in 10 countries, 62% were from the United States and 70% were male. Median age at the time of the survey was 33years, and median age at diagnosis was 9years. Patients saw a mean of 5 physicians from different specialties before their FCS diagnosis and experienced multiple physical, emotional, and cognitive symptoms on a daily to monthly basis; 40% were admitted to the hospital in the past year. A lifetime mean of 13 episodes occurred in the 40% of patients with FCS-related acute pancreatitis. Most patients (>90%) found managing fat intake to be difficult, and 53% experienced symptoms despite adherence to their diets. FCS impacted employment status (94%), emotional/mental well-being (58%-66%), and social relationships (68%-82%). Patients with FCS experience significant clinical and psychosocial burdens that reduce their quality of life and limit employment and social interactions. Increased awareness among healthcare professionals of the multifaceted nature of the FCS disease burden may help expedite diagnosis and timely institution of treatment and broaden management considerations.

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.

Laboratory investigations in lipidology

Advances in the causes of disorders of lipid metabolism, and effective intervention in atherosclerosis with medication, have increased the reliance on laboratory investigation in clinical practice. The conventional lipid profile, comprising fasting triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, suffices for screening persons at risk of atherosclerosis. Additionally, lipoprotein (a) measurement enhances risk assessment and could explain atherosclerosis with a desirable lipid profile. Certain rare disorders in sterol and fatty acid metabolism do not alter the conventional lipid profile. Non-fasting samples are gaining popularity, as the triglycerides, although mildly increased, signify atherogenic lipoprotein remnant accumulation. Apoprotein A1 (apo A1) and apo B concentrations parallel HDL cholesterol and LDL cholesterol, respectively, and are of value in disorders of these lipoproteins. In severe dyslipoproteinaemia, special investigations establish the cause of the disease and may allow selection of better treatment. In such cases, not only apoprotein concentrations, but also enzyme or cell function, as well as genetic investigations, are relevant. The most important genetic disorders to recognise are familial hypercholesterolaemia, dysbetalipoproteinaemia and chylomicronaemia. Expertise in lipidology is limited in South Africa, but specialist centres can provide clinical and laboratory support to ensure best management of severe disorders.

Laboratory investigations in lipidology

Advances in the causes of disorders of lipid metabolism, and effective intervention in atherosclerosis with medication, have increased the reliance on laboratory investigation in clinical practice. The conventional lipid profile, comprising fasting triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, suffices for screening persons at risk of atherosclerosis. Additionally, lipoprotein (a) measurement enhances risk assessment and could explain atherosclerosis with a desirable lipid profile. Certain rare disorders in sterol and fatty acid metabolism do not alter the conventional lipid profile. Non-fasting samples are gaining popularity, as the triglycerides, although mildly increased, signify atherogenic lipoprotein remnant accumulation. Apoprotein A1 (apo A1) and apo B concentrations parallel HDL cholesterol and LDL cholesterol, respectively, and are of value in disorders of these lipoproteins. In severe dyslipoproteinaemia, special investigations establish the cause of the disease and may allow selection of better treatment. In such cases, not only apoprotein concentrations, but also enzyme or cell function, as well as genetic investigations, are relevant. The most important genetic disorders to recognise are familial hypercholesterolaemia, dysbetalipoproteinaemia and chylomicronaemia. Expertise in lipidology is limited in South Africa, but specialist centres can provide clinical and laboratory support to ensure best management of severe disorders.

Examing the High Disease Burden and Impact on Quality of Life in Familial Chylomicronemia Syndrome †

Examing the High Disease Burden and Impact on Quality of Life in Familial Chylomicronemia Syndrome †

Evaluating the Impact of Peer Support and Connection on the Quality of Life of Patients with Familial Chylomicronemia Syndrome

Background: Familial chylomicronemia syndrome (FCS) is a disease caused by impaired lipoprotein lipase function and characterized by chylomicronemia, reduced quality of life (QoL) and risk of pancr...

FAMILIAL CHYLOMICRONEMIA SYNDROME: AN INSIGHT INTO ITS CLINICAL CHARACTERISTICS AND LONG TERM CARDIOVASCULAR OUTCOMES

Familial Chylomicronemia Syndrome (FCS) is a rare genetic dyslipidemia characterized by chylomicron and extreme triglyceride (Tg) elevation that is associated with pancreatitis risk. However, little is known about its clinical characteristics and long term outcomes. We retrospectively reviewed 70,

A novel mutation in GPIHBP1 causes familial chylomicronemia syndrome

Familial chylomicronemia syndrome is characterized by severe elevation in serum triglycerides and an increased risk of acute pancreatitis. Although familial chylomicronemia syndrome is mainly caused by mutations in the lipoprotein lipase (LPL) gene, few causal mutations in other genes (ie, APOC2, APOA5, LMF1, and GPIHBP1) have also been reported. In this case report, we present the discovery of a novel mutation in the glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) gene and discuss its pathogenicity through a familial segregation study.