Background: Familial chylomicronemia syndrome (FCS) is a rare inherited condition due to lipoprotein lipase deficiency, characterized by hyperchylomicronemia and severe hypertriglyceridemia. Diagnosis is often delayed, thus increasing the risk of acute pancreatitis and hospitalization. Hypertriglyceridemia is a common finding in patients with type 2 diabetes (T2D), who may harbor FCS among the most severe forms. Aim of the Study: We investigated the prevalence and clinical characteristics associated with severe hypertriglyceridemia in a range indicative of FCS, in a large population of subjects with T2D. Methods: Within the large population of the AMD Annals Initiative, patients with T2D with a lipid profile suggestive of FCS [triglycerides >880 mg/dL and/or high-density lipoprotein (HDL)-cholesterol <22 mg/dL or non-HDL-cholesterol ≤70 mg/dL] and their clinical features have been identified. Results: Overall, 8592 patients had triglyceride values >880 mg/dL in a single examination, 613 in two examinations, and 34 in three or more measurements. Patients with high triglyceride levels were mostly male (80%), with a relatively young age (54 years), short duration of diabetes (6.3 years), and elevated hemoglobin A1c (HbA1c) levels (9.4%). By stratifying this group of patients according to the severity of hypertriglyceridemia, more severe hypertriglyceridemia (triglyceride levels ≥2000 mg/dL) was associated with an even younger age (52 vs. 54 years), even higher mean HbA1c values (10.0% vs. 9.4%), and significantly higher HDL-cholesterol levels (37.9 vs. 32.4 mg/dL; P < 0.0001). Patients with persistently elevated triglyceride levels (n = 34), on three measurements, had a younger age; lower body mass index, HbA1c, and HDL-cholesterol levels; more frequent use of fibrates and insulin; and a higher prevalence of major cardiovascular events. Conclusions: Severe hypertriglyceridemia is a frequent condition in outpatients with T2D participating in the AMD Annals Initiative, and it is associated with male sex, young age, short disease duration, and a worse glycemic profile. Among patients with persistent severe hypertriglyceridemia, hidden FCS may be present.

Familial chylomicronemia syndrome (FCS) is a rare disorder of triglyceride (TG) metabolism caused by loss of function variants in one of five known canonical genes involved in chylomicron lipolysis and clearance-LPL, APOC2, APOA5, LMF1, and GPIHBP1. Pathogenic variants in LPL, which encodes the hydrolytic enzyme lipoprotein lipase, account for over 80%-90% of cases. FCS may present in infancy with hypertriglyceridemia-induced acute pancreatitis and is challenging to manage both acutely and in the long-term. Here, we report our experience managing two unrelated infants consecutively diagnosed with hypertriglyceridemia-induced acute pancreatitis caused by LPL deficiency. Both had elevated TGs at presentation (205 and 30 mmol/L, respectively) and molecular genetic testing confirmed each infant carried a different homozygous pathogenic variant in the LPL gene, specifically, c.987C>A (p.Tyr329Ter) and c.632C>A (p.Thr211Lys). The more severely affected infant had cutaneous xanthomata, lipemia retinalis and lipemic plasma at presentation, and required management in an intensive care setting. Acute stabilisation was achieved using insulin and heparin infusions together with the iterative implementation of a fat-restricted diet, low in long chain triglycerides (LCT) and supplemented with medium chain triglycerides (MCT). In both cases, provision of adequate caloric intake (~110-120 kcal/kg/day) was also found to be important for a sustained TG reduction during the acute phase of management. In summary, a high index of suspicion is required to diagnose FCS in infants with hypertriglyceridemia-induced acute pancreatitis, management of which can be challenging, highlighting the need for more evidence-based recommendations.

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.

UNASSIGNED: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive condition. Effective treatment is important as patients are at risk for severe and potentially fatal acute pancreatitis. We review recent developments in pharmacologic treatment for FCS, namely biological inhibitors of apolipoprotein (apo) C-III and angiopoietin-like protein 3 (ANGPTL3).
UNASSIGNED: FCS follows a biallelic inheritance pattern in which an individual inherits two pathogenic loss-of-function alleles of one of the five causal genes - LPL (in 60-80% of patients), GPIHBP1, APOA5, APOC2, and LMF1 - leading to the absence of lipolytic activity. Patients present from childhood with severely elevated triglyceride (TG) levels >10 mmol/L. Most patients with severe hypertriglyceridemia do not have FCS. A strict low-fat diet is the current first-line treatment, and existing lipid-lowering therapies are minimally effective in FCS. Apo C-III inhibitors are emerging TG-lowering therapies shown to be efficacious and safe in clinical trials. ANGPTL3 inhibitors, another class of emerging TG-lowering therapies, have been found to require at least partial lipoprotein lipase activity to lower plasma TG in clinical trials. ANGPTL3 inhibitors reduce plasma TG in patients with multifactorial chylomicronemia but not in patients with FCS who completely lack lipoprotein lipase activity.
UNASSIGNED: Apo C-III inhibitors currently in development are promising treatments for FCS.

Familial chylomicronemia syndrome (FCS) is one of the rare causes of hypertriglyceridemia. Plasmapheresis is recommended in patients with triglyceride levels greater than 2000 mg/dL. However, plasmapheresis is difficult to perform in most centers due to technical inadequacies in the neonatal period. There are some reports in the literature on the efficacy of exchange transfusion. The index case involves a 20-day-old male patient who was admitted to the emergency department for restlessness and poor feeding. He was born at term with a birth weight of 4000 g. He was exclusively breastfed. The patient was taken to the neonatal intensive care unit due to his plasma being in the form of excessive lipemia. The first measurable triglyceride level was 5100 mg/dL (57.6 mmol/L). Breast milk was restricted, and intravenous hydration was started. However, his triglyceride level did not decrease despite this treatment. Other laboratory values could not be read due to excessive lipemic serum. On the third day of hospitalization, an exchange transfusion was decided upon in this case due to the development of respiratory distress (oxygen support, tachypnea). After exchange transfusion, the patient\'s triglyceride level reduced dramatically to 592 mg/dL (6.6 mmol/L), and his respiratory symptoms resolved. The aim of this case report is to demonstrate that exchange transfusion therapy is a safe and effective treatment modality in the neonatal period for the acute management of FCS. Furthermore, dietary therapy restricted to long-chain fatty acids combined with medium-chain fatty acid supplementation is highly effective in the chronic management of these patients.

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.

Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, or metabolic syndromes. Looking into the genetic underpinnings of hypertriglyceridemia, this review focuses on the genetic variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1 triglyceride-regulating genes reportedly associated with abnormal genetic transcription and the translation of proteins participating in triglyceride-rich lipoprotein metabolism. Hypertriglyceridemia resulting from such genetic abnormalities can be categorized as monogenic or polygenic. Monogenic hypertriglyceridemia, also known as familial chylomicronemia syndrome, is caused by homozygous or compound heterozygous pathogenic variants in the five canonical genes. Polygenic hypertriglyceridemia, also known as multifactorial chylomicronemia syndrome in extreme cases of hypertriglyceridemia, is caused by heterozygous pathogenic genetic variants with variable penetrance affecting the canonical genes, and a set of common non-pathogenic genetic variants (polymorphisms, using the former nomenclature) with well-established association with elevated triglyceride levels. We further address recent progress in triglyceride-lowering treatments. Understanding the genetic basis of hypertriglyceridemia opens new translational opportunities in the scope of genetic screening and the development of novel therapies.

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disease affecting lipoprotein metabolism. FCS is estimated to occur in 1 in 1-2 million individuals and can be diagnosed at any age, equally affecting all genders, races, and ethnicities. The condition is characterized by hypertriglyceridemia, which may predispose patients to acute pancreatitis. In this report, we present the case of a now 6-year-old girl with FCS on gemfibrozil and dietary restrictions. The patient initially presented at 40 days of age with vomiting. Serum samples revealed lipemia, with markedly elevated triglyceride levels. The patient was diagnosed with FCS, confirmed by genetic testing showing the homozygous variant c.833C>T(p,Ser278Phe) for the LPL gene. Despite being on a low-fat diet with medium chain triglyceride (MCT) based milk formulas, the patient developed acute pancreatitis 2 months later with continued elevated triglyceride levels. She was placed on gemfibrozil and fat-soluble vitamins at 2 months of age, with marked improvements subsequently noted. Currently, the patient is doing well, with normal growth parameters and no other episodes of acute pancreatitis. Her triglyceride levels have been maintained within normal levels. FCS is a rare, inherited lipid disorder that often goes underdiagnosed and unmanaged. It is worth considering the fibric acid derivative (gemfibrozil) to be one of the lines of management early on after diagnosis.

BACKGROUND: Lipoprotein lipase (LPL) deficiency, the most common familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease characterized by chylomicronemia and severe hypertriglyceridemia (HTG), with limited clinical and genetic characterization.
OBJECTIVE: To describe the manifestations and management of 19 pediatric patients with LPL-FCS.
METHODS: LPL-FCS patients from 2014 to 2022 were divided into low-fat (LF), very-low-fat (VLF) and medium-chain-triglyceride (MCT) groups. Their clinical data were evaluated to investigate the effect of different diets. The genotype-phenotype relationship was assessed. Linear regression comparing long-chain triglyceride (LCT) intake and TG levels was analyzed.
RESULTS: Nine novel LPL variants were identified in 19 LPL-FCS pediatric patients. At baseline, eruptive xanthomas occurred in 3/19 patients, acute pancreatitis in 2/19, splenomegaly in 6/19 and hepatomegaly in 3/19. The median triglyceride (TG) level (30.3 mmol/L) was markedly increased. The MCT group and VLF group with LCT intakes <20 en% (energy percentage) had considerably lower TG levels than the LF group (both p<0.05). The LF group presented with severe HTG and significantly decreased TG levels after restricting LCT intakes to <20 en% (p<0.05). Six infants decreased TG levels to <10 mmol/L by keeping LCT intake <10 en%. TG levels and LCT intake were positively correlated in both patients under 2 years (r=0.84) and those aged 2-9 years (r=0.89). No genotype-phenotype relationship was observed.
CONCLUSIONS: This study broadens the clinical and genetic spectra of LPL-FCS. The primary therapy for LPL-FCS pediatric patients is restricting dietary LCTs to <10 en% or <20 en% depending on different ages. MCTs potentially provide extra energy.

BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare, hereditary, metabolic disorder. FCS causes high levels of triglycerides in the blood, which can lead to abdominal pain, xanthomas, and acute pancreatitis (AP). Volanesorsen, along with adherence to a very low-fat diet is used to reduce triglyceride levels in individuals with FCS. We aimed to understand the symptoms of FCS and their impact on health-related quality of life (HRQoL).
METHODS: Interviews were conducted with individuals with genetically confirmed FCS in the UK and Spain, some of whom had been treated with volanesorsen. Interview guides were developed with input from a patient advocacy group to explore the symptoms, impacts and management of FCS. Interviews were conducted by telephone and were recorded and transcribed. Data were analyzed using thematic analysis and saturation was recorded.
RESULTS: Seventeen interviews were conducted with individuals with FCS (aged 27-68 years), thirteen of whom were currently/previously treated with volanesorsen. Episodes of AP were the most impactful reported symptom, resulting in severe abdominal pain, nausea, vomiting, fever, bloating and appetite loss. Other symptoms and functional issues included abdominal pain, gastrointestinal symptoms, impaired cognitive function and fatigue. These had an impact on work, social activities, relationships and psychological wellbeing. These symptoms and impacts were illustrated in a conceptual model, including management strategies. The challenges of managing a low-fat diet and experience with volanesorsen were discussed.
CONCLUSIONS: Individuals with FCS experience a range of interrelated symptoms and functional limitations which impact their broader HRQoL. Treatments which alleviate symptoms and reduce the incidence of AP episodes have the potential to improve the HRQoL of these individuals.