Familial chylomicronemia syndrome in children: a diagnosis challenge.
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ABSTRACT:
SUBMITTER: Ariza MJ
PROVIDER: S-EPMC9732601 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
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Familial chylomicronemia syndrome in children: a diagnosis challenge.
Ariza María José MJ Valdivielso Pedro P
Translational pediatrics 20221101 11
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Project description: Not available
| S-EPMC9636463 | biostudies-literature
Project description:BackgroundFamilial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by persistent extreme hypertriglyceridemia as a result of lipoprotein lipase deficiency. Canada is an important region for FCS research due to the high prevalence rates. The burden of illness and quality of life of Canadian patients, however, have been inadequately addressed in the literature.ObjectiveTo understand the burden of illness of FCS on Canadian patients' lives.MethodsIN-FOCUS is a global web-based survey open to patients with FCS, including patients in Canada. This survey captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions.ResultsA total of 37 Canadian patients completed the IN-FOCUS survey. Patients saw a mean of 4 physicians before their FCS diagnosis despite 89% reporting an FCS family history. Patients experience multiple physical, emotional, and cognitive symptoms in addition to FCS-related comorbidities. Notably, 35% of those who answered the survey have experienced acute pancreatitis, averaging 14 lifetime episodes per patient. In the preceding 12 months, 46% of patients had an FCS-related hospitalization, averaging 3 nights' stay. All respondents restricted fat intake, with 27% following an extremely low-fat diet. Despite this, 100% of patients reported fasting TG levels above the normal range. FCS impacted career choice in nearly all patients (97%) and employment status in all patients who were employed part time, disabled, or homemakers, causing many (> 75%) to choose careers below their level of abilities. Furthermore, 2/3 of patients reported FCS had a significant impact on their decision regarding whether to have children. Most report significant interference with their emotional/mental well-being, social relationships, and the majority were concerned about the long-term impact of FCS on their health (89%).ConclusionsThis study provides the first and largest study to investigate the multi-faceted psychosocial and cognitive impacts of FCS on patients. Canadian patients with FCS experience significant multi-faceted burdens that diminish their quality of life, employment opportunities, social relationships, and mental/emotional well-being. These results highlight the need for greater disease awareness, improved clinical diagnosis, broader clinical management for heterogenous symptoms, and more effective treatment options for FCS.
| S-EPMC7268343 | biostudies-literature
Project description:BackgroundThere are no exact data about the prevalence of familial chylomicronemia syndrome (FCS) in Central Europe. We aimed to identify FCS patients using either the FCS score proposed by Moulin et al. or with data mining, and assessed the diagnostic applicability of the FCS score.MethodsAnalyzing medical records of 1,342,124 patients, the FCS score of each patient was calculated. Based on the data of previously diagnosed FCS patients, we trained machine learning models to identify other features that may improve FCS score calculation.ResultsWe identified 26 patients with an FCS score of ≥10. From the trained models, boosting tree models and support vector machines performed the best for patient recognition with overall AUC above 0.95, while artificial neural networks accomplished above 0.8, indicating less efficacy. We identified laboratory features that can be considered as additions to the FCS score calculation.ConclusionsThe estimated prevalence of FCS was 19.4 per million in our region, which exceeds the prevalence data of other European countries. Analysis of larger regional and country-wide data might increase the number of FCS cases. Although FCS score is an excellent tool in identifying potential FCS patients, consideration of some other features may improve its accuracy.
| S-EPMC9331828 | biostudies-literature
Project description: Not available
| S-EPMC11017581 | biostudies-literature
Project description:Background and aimFamilial 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.MethodsA 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.ResultsIn 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.ConclusionThis 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.
| S-EPMC10045250 | biostudies-literature
Project description:Purpose of reviewThis 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.
| S-EPMC8410715 | biostudies-literature
Project description:There are no adequate data that evaluate the safety and effectiveness of lowering triglyceride levels in very young children. The authors report a family with two male siblings, 7 and 4 years old, affected by familial hyperchylomicronemia. The oldest was diagnosed at birth during evaluation of jaundice, and the youngest showed asymptomatic hypertriglyceridemia by 6 months of age. Due to high triglyceride levels, Gemfibrozil (a fibric acid derivative) was started at diagnosis. Close clinical followup and laboratory monitoring of these children showed no side effects from the drug, and the risk of acute pancreatitis was significantly reduced.
| S-EPMC3014837 | biostudies-other
Project description:BackgroundFamilial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS.MethodsSix FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored.ResultsFollowing once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events.ConclusionThe novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease.Trial registrationClinicalTrials.gov identifier NCT01146522 .
| S-EPMC4337059 | biostudies-literature
Project description:Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher.PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-of-function mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive.The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life.Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease.Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.
| S-EPMC8532063 | biostudies-literature
Project description:BackgroundFamilial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS).MethodsThe study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project.ResultsFCS was relatively common in non-Europeans and those with parental consanguinity (P<0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P=0.001), recurrent pancreatitis (92% versus 63%; P<0.001), unexplained abdominal pain (84% versus 52%; P<0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P<0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P<0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS (P<0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS (P=0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS.ConclusionsThe frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS.
| S-EPMC11495541 | biostudies-literature