Clinical characterization and mutation spectrum of patients with hypertriglyceridemia in a German outpatient clinic.

BACKGROUND: Severe hypertriglyceridemia (HTG) has predominantly multifactorial causes (MCS). Yet a small subset of patients have the monogenetic form (FCS). It remains a challenge to distinguish patients clinically, since decompensated MCS might mimic FCS´s severity. Aim of the current study was to determine clinical criteria that could sufficiently distinguish both forms as well as to apply the FCS score proposed by Moulin and colleagues. METHODS: We retrospectively studied 72 patients who presented with severe HTG in our clinic during a time span of seven years and received genetic testing. We classified genetic variants (ACMG-criteria), followed by genetic categorization into MCS or FCS. Clinical data were gathered from the medical records and the FCS score was calculated for each patient. RESULTS: Molecular genetic screening revealed eight FCS patients and 64 MCS patients. Altogether, we found 13 pathogenic variants of which four have not been described before. The FCS patients showed a significantly higher median triglyceride level compared to the MCS. The FCS score yielded a sensitivity of 75% and a specificity of 93.7% in our cohort, and significantly differentiated between the FCS and MCS group (p<0.001). CONCLUSIONS: In our cohort we identified several variables that significantly differentiated FCS from MCS. The FCS score performed similar to the original study by Moulin, thereby further validating the discriminatory power of the FCS score in an independent cohort.

Significant but partial lipoprotein lipase functional loss caused by a novel occurrence of rare LPL biallelic variants.

BACKGROUND: Lipoprotein lipase (LPL) plays a crucial role in triglyceride hydrolysis. Rare biallelic variants in the LPL gene leading to complete or near-complete loss of function cause autosomal recessive familial chylomicronemia syndrome. However, rare biallelic LPL variants resulting in significant but partial loss of function are rarely documented. This study reports a novel occurrence of such rare biallelic LPL variants in a Chinese patient with hypertriglyceridemia-induced acute pancreatitis (HTG-AP) during pregnancy and provides an in-depth functional characterization. METHODS: The complete coding sequences and adjacent intronic regions of the LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes were analyzed by Sanger sequencing. The aim was to identify rare variants, including nonsense, frameshift, missense, small in-frame deletions or insertions, and canonical splice site mutations. The functional impact of identified LPL missense variants on protein expression, secretion, and activity was assessed in HEK293T cells through single and co-transfection experiments, with and without heparin treatment. RESULTS: Two rare LPL missense variants were identified in the patient: the previously reported c.809G > A (p.Arg270His) and a novel c.331G > C (p.Val111Leu). Genetic testing confirmed these variants were inherited biallelically. Functional analysis showed that the p.Arg270His variant resulted in a near-complete loss of LPL function due to effects on protein synthesis/stability, secretion, and enzymatic activity. In contrast, the p.Val111Leu variant retained approximately 32.3% of wild-type activity, without impacting protein synthesis, stability, or secretion. Co-transfection experiments indicated a combined activity level of 20.7%, suggesting no dominant negative interaction between the variants. The patient's post-heparin plasma LPL activity was about 35% of control levels. CONCLUSIONS: This study presents a novel case of partial but significant loss-of-function biallelic LPL variants in a patient with HTG-AP during pregnancy. Our findings enhance the understanding of the nuanced relationship between LPL genotypes and clinical phenotypes, highlighting the importance of residual LPL function in disease manifestation and severity. Additionally, our study underscores the challenges in classifying partial loss-of-function variants in classical Mendelian disease genes according to the American College of Medical Genetics and Genomics (ACMG)'s variant classification guidelines.

Inhibition of Angiopoietin-Like Protein 3 or 3/8 Complex and ApoC-III in Severe Hypertriglyceridemia.

PURPOSE OF REVIEW: The role of the inhibition of ANGPTL3 in severe or refractory hypercholesterolemia is well documented, less in severe hyperTG. This review focuses on the preclinical and clinical development of ApoC-III inhibitors and ANGPTL3, 4, and 3/8 complex inhibitors for the treatment of severe or refractory forms of hypertriglyceridemia to prevent cardiovascular disease or other morbidities. RECENT FINDINGS: APOC3 and ANGPTL3 became targets for drug development following the identification of naturally occurring loss of function variants in families with a favorable lipid profile and low cardiovascular risk. The inhibition of ANGPTL3 covers a broad spectrum of lipid disorders from severe hypercholesterolemia to severe hypertriglyceridemia, while the inhibition of ApoC-III can treat hypertriglyceridemia regardless of the severity. Preclinical and clinical data suggest that ApoC-III inhibitors, ANGPTL3 inhibitors, and inhibitors of the ANGPTL3/8 complex that is formed postprandially are highly effective for the treatment of severe or refractory hypertriglyceridemia. Inhibition of ANGPTL3 or the ANGPTL3/8 complex upregulates LPL and facilitates the hydrolysis and clearance of triglyceride-rich lipoproteins (TRL) (LPL-dependent mechanisms), whereas ApoC-III inhibitors contribute to the management and clearance of TRL through both LPL-dependent and LPL-independent mechanisms making it possible to successfully lower TG in subjects completely lacking LPL (familial chylomicronemia syndrome). Most of these agents are biologicals including monoclonal antibodies (mAb), antisense nucleotides (ASO), small interfering RNA (siRNA), or CRISPR-cas gene editing strategies.

Qualitative development of the PROMIS Profile v1.0-Familial Chylomicronemia Syndrome (FCS) 28.

PURPOSE: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by high triglyceride levels, significant disease burden, and negative impacts on health-related quality of life. This project aimed to create a PROMIS-based patient-reported outcome measure that represents valid and important concerns for patients with FCS. METHODS: We reviewed the literature and data from a previous qualitative study of FCS to identify key FCS symptoms and impacts, which were mapped to PROMIS domains to create a pool of eligible items. Candidate items were reduced per expert feedback and patients with FCS completed cognitive interviews to confirm content validity and measure content. RESULTS: Literature and qualitative data review identified ten key symptoms and 12 key impacts of FCS, including abdominal pain, fatigue, difficulty thinking, and worry about pancreatitis attacks. We identified 96 items primarily from PROMIS, supplemented with items from the Quality of Life in Neurological Disorders™ (Neuro-QoL™) and the Functional Assessment of Chronic Illness Therapy (FACIT) measurement systems. This pool was reduced to 32 candidate items, which were assessed via cognitive interviews with eight participants with FCS. Cognitive interview results and additional expert feedback led to the removal of four items and finalization of the PROMIS Profile v1.0-familial chylomicronemia syndrome (FCS) 28. CONCLUSIONS: The PROMIS Profile v1.0-familial chylomicronemia syndrome (FCS) 28 provides strong content validity for assessing quality of life among patients with FCS. The benefits of PROMIS, including norm-referenced mean values for each measure, will facilitate comparison of patients with FCS to other clinical populations.

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.

Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype-phenotype relationship for variants reported to date.

BACKGROUND: Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple heterozygous LPL variants are associated with hypertriglyceridemia (HTG) and HTG-related disorders. LPL frameshift coding sequence variants usually cause complete functional loss of the affected allele, thereby allowing exploration of the impact of different levels of LPL function in human disease. METHODS: All exons and flanking intronic regions of LPL were Sanger sequenced in patients with HTG-related acute pancreatitis (HTG-AP) or HTG-AP in pregnancy. Previously reported LPL frameshift coding sequence variants were collated from the Human Gene Mutation Database and through PubMed keyword searching. Original reports were manually evaluated for the following information: zygosity status of the variant, plasma LPL activity of the variant carrier, disease referred for genetic analysis, patient's age at genetic analysis, and patient's disease history. SpliceAI was employed to predict the potential impact of collated variants on splicing. RESULTS: Two novel rare variants were identified, and 53 known LPL frameshift coding sequence variants were collated. Of the 51 variants informative for zygosity, 30 were simple heterozygotes, 12 were homozygotes, and 9 were compound heterozygotes. Careful evaluation of the 55 variants with respect to their clinical and genetic data generated several interesting findings. First, we conclude that 6-7% residual LPL function could significantly delay the age of onset of FCS and reduce the prevalence of FCS-associated syndromes. Second, whereas a large majority of LPL frameshift coding sequence variants completely disrupt gene function through their "frameshift" nature, a small fraction of these variants may act wholly or partly as "in-frame" variants, leading to the generation of protein products with some residual LPL function. Third, we identified two candidate LPL frameshift coding sequence variants that may retain residual function based on genotype-phenotype correlation or SpliceAI-predicted data. CONCLUSIONS: This study reported two novel LPL variants and yielded new insights into the genotype-phenotype relationship as it pertains to LPL frameshift coding sequence variants.

Childhood Hypertriglyceridemia: Is It Time for a New Approach?

PURPOSE OF REVIEW: Hypertriglyceridemia (HTG) is widely prevalent in youth. There is an unmet need for effective medications in the management of HTG in youth. The purpose of this review is to summarize the approach to HTG in acute and chronic settings, and highlight emerging therapies targeted at specific genes, proteins, and enzymes to selectively alter triglyceride (TG) metabolism. RECENT FINDINGS: Genetic and lifestyle factors play a significant role in the pathophysiology of HTG. Severe elevation of TG poses a risk of acute pancreatitis, while mild-to-moderate HTG increases the risk for premature atherosclerotic cardiovascular disease (ASCVD) and, increasingly, has been linked with non-alcoholic fatty liver disease. Although a variety of therapeutic agents are in development, strict adherence to a heart healthy lifestyle, including dietary changes, remain the cornerstone of management for youth with HTG. In addition to lifestyle changes, pharmacological interventions, including fibrates, omega 3 fatty acids, and statins may be considered for management of moderate-to-severe HTG. In view of its association with premature cardiovascular disease (CVD), non-high-density-lipoprotein-C (non-HDL-C) is an important target for therapy in children with moderate HTG. Management of HTG is dependent on its etiology, concomitant symptoms, and degree of TG elevation. The last two decades have seen remarkable changes in drug development, specifically those that act through the lipoprotein lipase complex, including new targeted treatments such as inhibitors of apolipoprotein C3 and angiopoietin-like protein 3.

Prophylactic therapeutic plasma exchange in pregnant woman with Familial Chylomicronemia Syndrome - A case report.

CONTEXT: Familial Chylomicronemia Syndrome (FCS) is an inherited disease where lack of lipoprotein lipase results in severe hypertriglyceridemia that frequently leads to recurrent acute pancreatitis. Pregnancy in patients with familial chylomicronemia syndrome (FCS) post a risk for mother and baby with potential complications (pancreatitis, miscarriage and death). Therapeutic approach includes strict dietary measures and plasma exchange. Despite the development of new drugs for FCS, their safety in pregnancy has not yet been confirmed. CASE DESCRIPTION: We present a case of a young, pregnant female with FCS who had miscarriage in the past during one episode of acute pancreatitis. Due to the inability to achieve lower TG levels with current therapy, from 27-th week of pregnancy we have started prophylactic therapeutic plasma exchange (two times per week). Patient was followed up until the delivery of a healthy baby boy and did not experience an episode of acute pancreatitis. CONCLUSIONS: With adequate supervision and monitoring therapeutic plasma exchange represents a safe approach in pregnant women with FCS in order to reduce TGs and prevent pancreatitis. Therefore, we prevented potential complications for both mother and child.

Causes, clinical findings and therapeutic options in chylomicronemia syndrome, a special form of hypertriglyceridemia.

The prevalence of hypertriglyceridemia has been increasing worldwide. Attention is drawn to the fact that the frequency of a special hypertriglyceridemia entity, named chylomicronemia syndrome, is variable among its different forms. The monogenic form, termed familial chylomicronemia syndrome, is rare, occuring in 1 in every 1 million persons. On the other hand, the prevalence of the polygenic form of chylomicronemia syndrome is around 1:600. On the basis of the genetical alterations, other factors, such as obesity, alcohol consumption, uncontrolled diabetes mellitus and certain drugs may significantly contribute to the development of the multifactorial form. In this review, we aimed to highlight the recent findings about the clinical and laboratory features, differential diagnosis, as well as the epidemiology of the monogenic and polygenic forms of chylomicronemias. Regarding the therapy, differentiation between the two types of the chylomicronemia syndrome is essential, as well. Thus, proper treatment options of chylomicronemia and hypertriglyceridemia will be also summarized, emphasizing the newest therapeutic approaches, as novel agents may offer solution for the effective treatment of these conditions.

A lipoprotein lipase-GPI-anchored high-density lipoprotein-binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome.

Lipoprotein lipase (LPL) is central to triglyceride metabolism. Severely compromised LPL activity causes familial chylomicronemia syndrome (FCS), which is associated with very high plasma triglyceride levels and increased risk of life-threatening pancreatitis. Currently, no approved pharmacological intervention can acutely lower plasma triglycerides in FCS. Low yield, high aggregation, and poor stability of recombinant LPL have thus far prevented development of enzyme replacement therapy. Recently, we showed that LPL monomers form 1:1 complexes with the LPL transporter glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) and solved the structure of the complex. In the present work, we further characterized the monomeric LPL/GPIHBP1 complex and its derivative, the LPL-GPIHBP1 fusion protein, with the goal of contributing to the development of an LPL enzyme replacement therapy. Fusion of LPL to GPIHBP1 increased yields of recombinant LPL, prevented LPL aggregation, stabilized LPL against spontaneous inactivation, and made it resistant to inactivation by the LPL antagonists angiopoietin-like protein 3 (ANGPTL3) or ANGPTL4. The high stability of the fusion protein enabled us to identify LPL amino acids that interact with ANGPTL4. Additionally, the LPL-GPIHBP1 fusion protein exhibited high enzyme activity in in vitro assays. Importantly, both intravenous and subcutaneous administrations of the fusion protein lowered triglycerides in several mouse strains without causing adverse effects. These results indicate that the LPL-GPIHBP1 fusion protein has potential for use as a therapeutic for managing FCS.

Rare Treatments for Rare Dyslipidemias: New Perspectives in the Treatment of Homozygous Familial Hypercholesterolemia (HoFH) and Familial Chylomicronemia Syndrome (FCS).

PURPOSE OF REVIEW: This review aims to summarize the most recent published literature concerning lomitapide and volanesorsen that are approved for the use in HoFH and FCS patients, respectively. Moreover, it will briefly revise the published evidence on novel, non-approved treatments that are under evaluation for the management of these rare forms of dyslipidemias RECENT FINDINGS: The definition of rare dyslipidemias identifies a large number of severe disorders of lipid metabolism of genetic origin. Among them were homozygous familial hypercholesterolemia (HoFH) (OMIM #143890) and familial chylomicronemia syndrome (FCS) (OMIM #238600), which are characterized by a markedly impaired cholesterol- and triglyceride-containing lipoproteins metabolism. They are being particularly associated with poor health outcomes and quality of life. Considering the severity of these diseases, common lipid-lowering drugs are often ineffective or do not allow to achieve the recommended lipid targets to prevent the development of complications. Nowadays, several new drugs have been found to effectively treat HoFH and FCS with an acceptable safety profile. Treating patients with HoFH and FCS remains very challenging. However, novel treatment options are emerging and might be considered in addition to conventional therapy for managing these diseases. These novel drugs will possibly change the natural history of these two rare and life-threatening diseases.

THE PREVALENCE OF PROBABLE FAMILIAL CHYLOMICRONEMIA SYNDROME IN A SOUTHERN CALIFORNIA POPULATION.

OBJECTIVE: To estimate the prevalence of probable familial chylomicronemia syndrome (FCS) in a major Southern California Academic Center as well as to provide a systematic review of past FCS studies and management recommendations. METHODS: Electronic medical records were queried based on single fasting plasma triglyceride (TG) levels of ≥880 mg/dL and at least 1 episode of acute pancreatitis. After the exclusion of secondary causes (diabetes, alcohol misuse, gallbladder disease, chronic kidney disease, uncontrolled hypothyroidism, estrogen, and drug use) and responses to lipid-lowering treatment, probable patients with FCS were identified. A systematic review of all published literature on the prevalence and management guidelines for FCS was then presented and discussed. RESULTS: Out of 7 699 288 charts queried, 138 patients with TG levels of ≥880 mg/dL and documented evidence of at least 1 episode of acute pancreatitis were identified. Nine patients did not have any documented secondary causes of chylomicronemia. Four of the 9 patients had >20% decrease in TG levels after lipid-lowering treatment, 2 patients were not responsive to lipid-lowering medication, and data on lipid-lowering medications were missing in 3 patients. CONCLUSION: Our study estimates the prevalence of probable FCS at a range of 0.26 to 0.66 per million. Using the recommended criteria, probable FCS cases can be identified to allow early diagnosis and management.

Familial hypertriglyceridemia: an entity with distinguishable features from other causes of hypertriglyceridemia.

BACKGROUND: Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. METHODS: This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. RESULTS: Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901-0.970, 98.5% sensitivity, 92.2% specificity, P < 0.001). The polygenic set of SNPs, accounted for 1.78% of the variance in triglyceride levels in FHTG and 6.73% in CHTG. CONCLUSIONS: The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.

Management strategy and novel ophthalmological findings in neonatal severe hypertriglyceridemia: a case report and literature review.

BACKGROUND: Neonatal severe hypertriglyceridemia is rarely reported in the literature and there is no consensus for hypertriglyceridemia management at this age group. METHODS: The index case is a 4-week-old male infant with severe hypertriglyceridemia accidentally discovered during a circumcision surgery. His clinical and genetic characteristics and his successful management strategy are described. Furthermore, a detailed ophthalmological examination of the proband was conducted at 3 and 6 months of age using Fourier-domain-optical coherence tomography. RESULTS: Triglycerides level at presentation was extremely high 33,727 mg/dL (380.8 mmol/L). Two sessions of exchange blood transfusion on two consecutive days successfully reduced triglycerides to 382 mg/dL (4.3 mmol/L) with no adverse effects. The infant was discharged 3 days later. At discharge, the mother was advised to continue breastfeeding together with a medium-chain triglycerides formula. Satisfactory growth parameters and lipid profile values were obtained for a follow-up duration of 5 months with no reported attacks of acute pancreatitis. Lipoprotein lipase deficiency was confirmed by the detection of the LPL homozygous pathogenic variant c.805G > A; p.(Glu269Lys). Early corneal and macular lesions were detected and persisted on follow-up despite relatively good lipemic control. CONCLUSION: This case highlights the importance of the early discovery of severe hypertriglyceridemia during the neonatal period, which is needed for prompt management and prevention of severe complications. Rationalized breastfeeding can be tolerated within the diet plan of the disease with satisfactory outcomes. To our knowledge, it is the first study reporting early corneal and macular affection by severe hypertriglyceridemia in a neonate. Prolonged follow-up is needed to determine the extent of ophthalmological lesions.

A Case of Glycogen Storage Disease Type 1a Mimicking Familial Chylomicronemia Syndrome.

Glycogen storage disease type 1a (GSD1a) is an autosomal recessively inherited inborn error of metabolism caused by a mutation in the G6PC gene, which encodes the catalytic subunit of glucose-6-phosphatase-α (G6Pase-α) enzyme. This enzyme plays a role in the final step of gluconeogenesis and glycogenolysis. Patients carrying GSD1a show growth retardation, hypoglycemia, hepatomegaly, hepatic steatosis, hyperlipidemia, hyperuricemia and lactic acidemia. Long-term symptoms include gouty arthritis and uric acid stones, osteoporosis, renal failure, intestinal impairment, cirrhosis and hepatic adenomas, and eventually, hepatocellular carcinoma. Hyperlipidemia is the indicator of poor metabolic control in GSD1a. Patients with variable levels of triglycerides (TGs) have been reported in the literature. We present a case of GSD1a that presented with severe hypertriglyceridemia (HTG) mimicking familial chylomicronemia syndrome.

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 (>10 mmol L-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.

Marked effects of novel selective peroxisome proliferator-activated receptor α modulator, pemafibrate in severe hypertriglyceridemia: preliminary report.

BACKGROUND: Currently available treatments have only been partly successful in patients with severe hypertriglyceridemia, including those with high serum triglycerides above 1,000 mg/dL (11.3 mmol/L), who often suffer from acute pancreatitis. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) which has been developed as an affordable oral tablet in Japan. We herein report the first three patients with severe hypertriglyceridemia who were successfully treated with pemafibrate. METHODS: Three patients with fasting serum triglyceride (TG) levels above 1,000 mg/dL (11.3 mmol/L) were treated with pemafibrate (0.2-0.4 mg/day, 0.1-0.2 mg BID). RESULTS: Serum TGs decreased from 2,000-3,000 mg/dL (22.6-33.9 mmol/L) to < 250 mg/dL (2.8 mmol/L) without adverse effects in all three patients. Serum TGs in Patient 1 and 2 decreased from 1,326 mg/dL (15.0 mmol/L) to 164 mg/dL (1.9 mmol/L) and from 2,040 mg/dL (23.1 mmol/L) to 234 mg/dL (2.6 mmol/L), respectively. Patient 3 with type 2 diabetes and 12.1% (109 mmol/mol) hemoglobin A1c had a TG level of 2,300 mg/dL (26.0 mmol/L). Even after glycemic control improved, TG remained high. After pemafibrate administration, TG decreased to 200 mg/dL (2.3 mmol/L). All patients showed no serious adverse events. CONCLUSIONS: Pemafibrate demonstrated potential efficacy and safety for severe hypertriglyceridemia which may contribute to the prevention of acute pancreatitis, in a manner that can be easily prescribed and used as an oral tablet.

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

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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.

Successful management of acute pancreatitis due to apolipoprotein C-II deficiency in a 37-day-old infant.

Familial chylomicronemia is caused by deficiency of lipoprotein lipase or its co-activators. Here, we report an infant with apolipoprotein C-II (APOC2) deficiency, who developed acute pancreatitis 37 days after birth. He presented as abdominal sepsis with fever, irritability and abdominal distention. Amylase levels were low, but lipase levels and imaging findings were consistent with acute pancreatitis. He had severe hypertriglyceridemia (1091 mg/dl). Keeping him nil orally for two days resulted in rapid decrease in triglyceride levels and resolution of the clinical findings. APOC2 gene sequencing revealed a homozygous splice-site mutation (c.55+1G>C). To the best of our knowledge, this patient is not only the youngest reported patient with APOC2 deficiency, but also the youngest such patient who developed pancreatitis. Although he had a severe presentation, invasive methods to treat hypertriglyceridemia were not necessary. We emphasize that clinical findings and amylase levels are not reliable to diagnose pancreatitis in this age group.

Management of a pregnant patient with chylomicronemia from a novel mutation in GPIHBP1: a case report.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive lipid disorder often associated with recurrent episodes of pancreatitis. It is documented in most cases with FCS due to the mutations of key proteins in lipolysis, including LPL, APOC2, APOA5, LMF1 and GPIHBP1. CASE PRESENTATION: We report the successful management of a 35-year-old pregnant woman carrying a novel homozygous frameshift mutation c.48_49insGCGG (p.P17A fs*22) in the GPIHBP1 gene with previous severe episodes of acute pancreatitis triggered by pregnancy, resulting in adverse obstetrical outcomes. With careful monitoring, the patient underwent an uneventful pregnancy and delivered a baby with no anomalies. CONCLUSIONS: The case report contributes to the understanding of GPIHBP1-deficient familial chylomicronemia syndrome (FCS) and highlights gestational management of FCS patient.