Lipoprotein Lipase Deficiency Research Articles

Prevalence of familial chylomicronemia syndrome in a quaternary care center.

Prevalence of familial chylomicronemia syndrome in a quaternary care center.

Kinetics of triglyceride decrease during hospitalisation for major hyperchylomicronemia in multifactorial chylomicronemia syndrome

Kinetics of triglyceride decrease during hospitalisation for major hyperchylomicronemia in multifactorial chylomicronemia syndrome

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.

Whole exome sequencing for non-selective pediatric patients with hyperlipidemia.

Hyperlipidemia is a group of conditions with abnormally elevated levels of any or all lipids or lipoproteins in the blood. It is highly heterogeneous both genetically and clinically, which contributes to diagnostic challenges and results in many patients to be underdiagnosed and undertreated in China. Precise diagnosis and early management are critical to reduce the incidence of potential coronary artery disease and cardiovascular disease. We performed a single center study to demonstrate the clinical utility of the genome-first approach by whole exome sequencing (WES) for 12 pediatric patients with abnormal lipids or lipoproteins levels. In vitro experiments were performed in COS-7 cells to further evaluate the biological function of the novel variants. We identified ten pathogenic and likely pathogenic variants and three of them were novel. Molecular cause was uncovered in five (41.7%) patients including three lipoprotein lipase deficiency patients, one hypercholesterolemia patient and one sitosterolemia patient. We also found three patients with rare variants of uncertain significance. Copy number variant (CNV) analysis with WES data did not reveal any potential hyperlipidemia related CNVs in all patients. We expanded the mutation and phenotype spectra of familial hyperlipidemia. Our study demonstrated the effectiveness of genome-first approach for evaluation pediatric hyperlipidemia patients and showed that WES can be used as the first-tier test for patients with suspected Mendelian hyperlipidemia disorder.

A Comprehensive Update on the Chylomicronemia Syndrome.

The chylomicronemia syndrome is characterized by severe hypertriglyceridemia and fasting chylomicronemia and predisposes affected individuals to acute pancreatitis. When due to very rare monogenic mutations in the genes encoding the enzyme, lipoprotein lipase, or its regulators, APOC2, APOA5, GPIHBP1, and LMF1, it is referred to as the familial chylomicronemia syndrome. Much more frequently, the chylomicronemia syndrome results from a cluster of minor genetic variants causing polygenic hypertriglyceridemia, which is exacerbated by conditions or medications which increase triglyceride levels beyond the saturation point of triglyceride removal systems. This situation is termed the multifactorial chylomicronemia syndrome. These aggravating factors include common conditions such as uncontrolled diabetes, overweight and obesity, alcohol excess, chronic kidney disease and pregnancy and several medications, including diuretics, non-selective beta blockers, estrogenic compounds, corticosteroids, protease inhibitors, immunosuppressives, antipsychotics, antidepressants, retinoids, L-asparaginase, and propofol. A third uncommon cause of the chylomicronemia syndrome is familial forms of partial lipodystrophy. Development of pancreatitis is the most feared complication of the chylomicronemia syndrome, but the risk of cardiovascular disease as well as non-alcoholic steatohepatitis is also increased. Treatment consists of dietary fat restriction and weight reduction combined with the use of triglyceride lowering medications such as fibrates, omega 3 fatty acids and niacin. Effective management of aggravating factors such as improving diabetes control, discontinuing alcohol and replacing or reducing the dose of medications that raise triglyceride levels is essential. Importantly, many if not most cases of the chylomicronemia syndrome can be prevented by effective identification of polygenic hypertriglyceridemia in people with conditions that increase its likelihood or before starting medications that may increase triglyceride levels. Several new pharmacotherapeutic agents are being tested that are likely to considerably improve treatment of hypertriglyceridemia in people at risk.

S1423 Lipoprotein Lipase Deficiency as a Rare Cause of Acute Pancreatitis

INTRODUCTION: Hypertriglyceridemia (HTG)-induced pancreatitis comprises 1 to 14 % of all cases of acute pancreatitis. Generally, primary HTG refers to a genetic disorder that includes type 1, 4 and 5 dyslipidemia. Familial lipoprotein lipase (LPL) deficiency is a rare condition of primary HTG with autosomal recessive transmission and a prevalence of 1-2:1,000,000. This case describes a patient with acute pancreatitis attributed secondary to LPL deficiency. CASE DESCRIPTION/METHODS: A 28 year old female with a history of type 1 diabetes mellitus complicated by diabetic gastroparesis s/p gastrojejunal bypass, HTN, HTG, recurrent pancreatitis presented to ED with abdominal pain. She had numerous admissions in the past due to recurrent pancreatitis secondary to HTG , one of which was complicated by necrotizing pancreatitis and wall off necrosis for which she underwent partial pancreatectomy. The patient also has an extensive family history of early onset type 1 diabetes and HTG. Despite the use of high intensity statin, fenofibrate, diet restriction and insulin pump, triglyceride levels has been very difficult to control. On physical examination, multiple red-yellowish bumps are noted on the arms consistent with xathomas. Labs were significant for elevated triglycerides and lipase (4500 and 400 respectively). Abdomen and pelvis CT scan showed evidence suggestive of acute pancreatitis, splenic vein thrombosis and hepatosplenomegaly. Due to high suspicion, molecular genetic testing for LPL deficiency was sent and came back positive. DISCUSSION: Patients with LPL are classically found to have high serum plasma triglycerides, low HDL-cholesterol, and presence of fasting chylomicrons in the plasma due to mutation of the enzyme that is responsible for hydrolysis and removal of triglycerides from the plasma. The most feared complication of the disease is recurrent and potentially life threatening acute pancreatitis. Although this is a very rare condition, it is an important differential diagnosis to consider due to refractoriness of conventional medical therapies including statins, fibrates and reduced fat intake(less than 20 g/day). There have been some studies that suggested high dose antioxidant therapy could potentially help lower the level of triglycerides and prevent recurrent episodes of acute pancreatitis in that particular group of patients. It is also critical to make the diagnosis as soon as possible for early medical interventions during childhood and genetic counseling and testing for family members.

Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism.

The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here, we show that, despite obesity, mice with reduced neuronal LPL (NEXCreLPLflox (LPL KD)) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to wilt type (WT) controls (LPLflox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence lifetime imaging microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of free vs. bound nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in or over-expressing LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver-related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism.

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.

A Rare Disease of Familial Chylomicronemia Syndrome in a 20 Days Infant

Familial chylomicronemia syndrome is a group of very rare genetic disorders. It is inherited as autosomal recessive disorder. Its estimated incidence is 1 in 1000000 populations, characterized by deficient activity of an enzyme lipoprotein lipase (LPL) or apo-protein C-II, resulting into severe fasting hypertriglyceridemia and massive accumulations of chylomicrons in plasma. LPL deficiency typically presents in childhood with failure to thrive, colicky abdominal pain, eruptive xanthomas, lipemiaretinalis, pancreatitis and hepatomegaly. We are reporting a rare case of familial chylomicronemia in a 20 days old child who was presented with pneumonia, his plasma incidentally found like milk during routine collection of his blood sample. As the child was only 20 days old with very high triglyceride level, so breast feeding continued and cocktail therapy with low dose Tablet Fenofibrate, Tablet Niacin, Tablet Atovastatin started after referral to paediatric cardiologist at 3 months of age.&#x0D; Journal of Armed Forces Medical College Bangladesh Vol.15 (1) 2019: 107-109

Evaluation of the chylomicron-TG to VLDL-TG ratio for type I hyperlipoproteinemia diagnostic.

The aim of this study is to confirm the diagnostic performance of the Chylomicron to very low-density lipoproteins triglycerides (CM/VLDL-TG) ratio, the triglycerides to cholesterol ratio (TG/TC) and a dichotomic rule including the tryglycerides to apolipoprotein B (TG/APOB) ratio for the presence of Type I hyperlipoproteinemia (HPLI) in patients with severe hypertriglyceridemia (sHTG) that were at high risk for familial chylomicronemia syndrome (FCS). Two cohorts (derivation and validation) of patients with sHTG were included in the study. Anthropometric, clinical, biochemical and genetic data were obtained. The CM/VLDL-TG, TG/TC and TG/APOB ratios were calculated. Finally, a diagnostic performance study was developed to establish sensitivity, specificity and cut-offs by a ROC curve analysis in the derivation cohort as well as agreement and predictive values in the validation cohort. Patients with FCS in both cohorts showed an earlier presence in pancreatitis, greater number of acute pancreatitis episodes and lower BMI. FCS patients also showed higher ratios of CM/VLDL-TG, TG/TC and TG/APOB ratios, whereas their HDL-C, LDL-C and APOB levels were lower than in non-FCS patients. Sensitivity and agreement were low for both the TG/TC and TG/APOB ratios, although predictive values were good. The CM/VLDL-TG ratio showed greatest sensitivity, specificity, agreement and predictive values for cut-off of 3.8 and 4.5. Our results suggest that in subjects at high risk of FCS a total serum TG/TC ratio or TG/APOB ratio are feasible to initially screen for HLPI; however, a CM/VLDL-TG ratio ≥4.5 is a better diagnostic criterion for HPLI.

2019 George Lyman Duff Memorial Lecture: Three Decades of Examining DNA in Patients With Dyslipidemia.

Dyslipidemias include both rare single gene disorders and common conditions that have a complex underlying basis. In London, ON, there is fortuitous close physical proximity between the Lipid Genetics Clinic and the London Regional Genomics Centre. For >30 years, we have applied DNA sequencing of clinical samples to help answer scientific questions. More than 2000 patients referred with dyslipidemias have participated in an ongoing translational research program. In 2013, we transitioned to next-generation sequencing; our targeted panel is designed to concurrently assess both monogenic and polygenic contributions to dyslipidemias. Patient DNA is screened for rare variants underlying 25 mendelian dyslipidemias, including familial hypercholesterolemia, hepatic lipase deficiency, abetalipoproteinemia, and familial chylomicronemia syndrome. Furthermore, polygenic scores for LDL (low-density lipoprotein) and HDL (high-density lipoprotein) cholesterol, and triglycerides are calculated for each patient. We thus simultaneously document both rare and common genetic variants, allowing for a broad view of genetic predisposition for both individual patients and cohorts. For instance, among patients referred with severe hypertriglyceridemia, defined as ≥10 mmol/L (≥885 mg/dL), <1% have a mendelian disorder (ie, autosomal recessive familial chylomicronemia syndrome), ≈15% have heterozygous rare variants (a >3-fold increase over normolipidemic individuals), and ≈35% have an extreme polygenic score (a >3-fold increase over normolipidemic individuals). Other dyslipidemias show a different mix of genetic determinants. Genetic results are discussed with patients and can support clinical decision-making. Integrating DNA testing into clinical care allows for a bidirectional flow of information, which facilitates scientific discoveries and clinical translation.

Genetics of Hypertriglyceridemia.

Hypertriglyceridemia, a commonly encountered phenotype in cardiovascular and metabolic clinics, is surprisingly complex. A range of genetic variants, from single-nucleotide variants to large-scale copy number variants, can lead to either the severe or mild-to-moderate forms of the disease. At the genetic level, severely elevated triglyceride levels resulting from familial chylomicronemia syndrome (FCS) are caused by homozygous or biallelic loss-of-function variants in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes. In contrast, susceptibility to multifactorial chylomicronemia (MCM), which has an estimated prevalence of ~1 in 600 and is at least 50–100-times more common than FCS, results from two different types of genetic variants: (1) rare heterozygous variants (minor allele frequency <1%) with variable penetrance in the five causal genes for FCS; and (2) common variants (minor allele frequency >5%) whose individually small phenotypic effects are quantified using a polygenic score. There is indirect evidence of similar complex genetic predisposition in other clinical phenotypes that have a component of hypertriglyceridemia, such as combined hyperlipidemia and dysbetalipoproteinemia. Future considerations include: (1) evaluation of whether the specific type of genetic predisposition to hypertriglyceridemia affects medical decisions or long-term outcomes; and (2) searching for other genetic contributors, including the role of genome-wide polygenic scores, novel genes, non-linear gene-gene or gene-environment interactions, and non-genomic mechanisms including epigenetics and mitochondrial DNA.

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.

Evaluation of efficacy and safety of antisense inhibition of apolipoprotein C-III with volanesorsen in patients with severe hypertriglyceridemia

ABSTRACT Introduction Severe hypertriglyceridemia (sHTG) is a complex disorder of lipid metabolism characterized by plasma levels of triglyceride (TG) greater than 885 mg/dl (>10 mmol/L). The treatment of sHTG syndromes is challenging because conventional treatments are often ineffective in reducing TG under the threshold to prevent acute pancreatitis (AP). The inhibition of APOC3, which encodes a protein involved in triglyceride (TG)-rich lipoproteins (TGRLs) removal, has been reported to be a novel target for the treatment of sHTG. Volanesorsen is a second-generation antisense oligonucleotide inhibiting apoC-III transcription/translation that has been recently approved in Europe for Familial Chylomicronemia Syndrome (FCS) treatment. Areas covered This review summarizes the evidences on the efficacy and safety of volanesorsen for the treatment of sHTG syndromes. Expert opinion Volanesorsen effectively reduces TG in sHTG through a mechanism that is mainly LPL-independent, potentially decreasing the risk of AP. Some safety concerns have been raised with the use of volanesorsen, mainly represented by the occurrence of thrombocytopenia. Due to the potential severity of side effects, some caution is needed before affirming the long-term utility of this drug. Despite this, volanesorsen currently remains the only drug that has been demonstrated effective in FCS, which otherwise remains an untreatable disease.

Estimating health state utilities associated with a rare disease: familial chylomicronemia syndrome (FCS)

Aims: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder with no currently approved therapies. Treatments are in development, and cost-utility analyses will be needed to examine their value. These models will require health state utilities representing FCS. Therefore, the purpose of this study was to estimate utilities for FCS and an associated episode of acute pancreatitis (AP).Methods: Because it is not feasible to gather a large enough sample of patients with this extremely rare condition to complete standardized preference-based measures, vignette-based methods were used to estimate utilities. In time trade-off interviews, general population participants in the UK and Canada valued health state vignettes drafted based on literature review, clinician input, and interviews with patients. Four health states described variations of FCS. A fifth health state, describing AP, was added to one of the other health states to evaluate its impact on utility.Results: A total of 308 participants provided utility data (208 UK; 100 Canada). Mean utilities for FCS health states ranged from 0.46 to 0.83, with higher triglycerides, more severe symptoms, and a history of AP associated with lower utility values. The disutility (i.e. utility decrease) of AP ranged from –0.17 to –0.25, with variations depending on the health state to which it was added. Utility means were similar in the UK and Canada.Conclusions: The vignette-based approach is useful for estimating utilities of a rare disease. The health state utilities derived in this study would be useful in models examining cost-effectiveness of treatments for FCS.

Volanesorsen in the Treatment of Familial Chylomicronemia Syndrome or Hypertriglyceridaemia: Design, Development and Place in Therapy.

Severe hypertriglyceridaemia is associated with pancreatitis and chronic pancreatitis-induced diabetes. Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder of lipid metabolism characterised by high levels of triglycerides (TGs) due to failure of chylomicron clearance. It causes repeated episodes of severe abdominal pain, fatigue and attacks of acute pancreatitis. There are few current options for its long-term management. The only universal long-term therapy is restriction of total dietary fat intake to <10-15% of daily calories (15 to 20g per day). Many patients have been treated with fibrates and statins with a variable response, but many remain susceptible to pancreatitis. Other genetic syndromes associated with hypertriglyceridaemia include familial partial lipodystrophy (FPLD). Targeting apolipoprotein C3 (apoC3) offers the ability to increase clearance of chylomicrons and other triglyceride-rich lipoproteins. Volanesorsen is an antisense oligonucleotide (ASO) inhibitor of apoC3, which reduces TG levels by 70–80% which has been shown also to reduce rates of pancreatitis and improve well-being in FCS and reduce TGs and improve insulin resistance in FPLD. It is now undergoing licensing and payer reviews. Further developments of antisense technology including small interfering RNA therapy to apoC3 as well as other approaches to modulating triglycerides are in development for this rare disorder.

PROMIS Measure Captures Perceived Cognitive Impairment Associated with Familial Chylomicronemia Syndrome

Rina S. Fox completed this work as contracted by Akcea Therapeutics

How does Burden of Illness of Familial Chylomicronemia Syndrome Patients Compare to a General Population cohort? Results of a PSM study

M. Davidson is a scientific advisory board member of Abbott, Amgen, AstraZeneca, Merck and Sanofi, Regeneron.

Development of a Novel Patient-Reported Outcome Measure for Symptoms and Impacts of Familial Chylomicronemia Syndrome

Nothing to disclose.