Molecular basis of the familial chylomicronemia syndrome in patients from the National Dyslipidemia Registry of the Spanish Atherosclerosis Society

Ariza, M.J.; Rioja, José; Ibarretxe, Daiana; Camacho, Ana; Díaz‐Díaz, José Luis; Mangas, Alipio; Carbayo-Herencia, Julio Antonio; Ruiz-Ocaña, Pablo; Lamíquiz-Moneo, Itziar; Mosquera, Daniel; Sáenz, Pedro Luis Ruiz; Masana, L.; Muñiz-Grijalvo, Ovidio; Valdivielso, Pedro; Tembra, M. Suárez; Iglesias, Gonzalo Pías; Herencia, Julio A. Carbayo; Buitrago, Claudia; Vilá, Luis M.; Coca, Camila; Rocabruna, E. Llargués; Castillo, Vásquez; Pedro-Botet, J; Climent, Elisenda; Pont, Marta Mauri; Pintó, Xavier; Victoria, Elsy; Amor, J; Rados, Danijela; Blanco‐Vaca, Francisco; Lozano, José M.; Jiménez, F.J. Fuentes; Soler, Isabel Orea; Ferrer, Claudia; Cervantes, A.; Belmonte, A.; Mogollón, F.J. Novoa; Sánchez-Hernández, Rosa; Montesdeoca, A.B. Expósito; Jiménez, Manuel Jesús Romero; García, M.P. González; Bueno, Marta; Hernando, Ángel; Lahoz, Carlos; Prieto, José M. Mostaza; Núñez-Cortés, Jesús Millán; García, L. Reinares; Echevarría, Agustín Blanco; Ariza, María José; Villodres, José Rioja; Sánchez-Chaparro, Miguel Ángel; Chaparro, S. Jansen; Aranzubía, Pedro Sáenz de; Mateu, Emilia; Múgica, Fernando; Grijalvo, Ovidio Muñiz; Martin, Lynn; Plana, Núria; Gerediaga, D. Ibarretxe; Rodríguez-Borjabad, Cèlia; Lopez, Sabine; Mijares, Antonio Hernández; Gimilio, Juan Francisco Ascaso; García, Lourdes Pérez; Murillo, F. Civeira; Pérez-Calahorra, Sofía; Lamiquiz-Moneo, I.; Gallego, Rocío; Benedí, V. Marco; Vela, Juan Ferrando

doi:10.1016/j.jacl.2018.07.013

Cited by 25 publications

(17 citation statements)

References 64 publications

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“…The mutations in LPL and GPIHBP1 harboured by the FCS patients in both Derivation and Validations Cohorts were reported 18,19 . The absence of pathogenic variants in the non‐FCS patients from the derivation cohort was confirmed by NGS sequencing (Illumina).…”

Section: Methodsmentioning

confidence: 88%

“…The TG/TC, CM/VLDL‐TG and the TG/APOB ratios were higher in patients with FCS than in non‐FCS, since those patients have more chylomicron but moderate to normal VLDL‐TG levels 28 . Furthermore, the non‐FCS patient group showed a median TG lower than patients with FCS presumably in part because of the positive effect of the lipid lowering therapy, which is not effective in patients with FCS 18 …”

Section: Discussionmentioning

confidence: 96%

“…The diagnosis of FCS, a rare disease, in subjects with severe hypertriglyceridemia is challenging for clinicians as well for laboratories. Several clinical features point to FCS, such as low body mass index and recurrent acute hypertriglyceridemic pancreatitis especially at young age 9,18,24,25 . In fact, in one study, the age at first symptom, body mass index and serum levels of gamma‐glutamyl transferase (GGT) were predictors of FCS in univariate and age‐ and sex‐ adjusted analyses 25 .…”

Section: Discussionmentioning

confidence: 99%

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

Rioja

Ariza

García‐Casares

et al. 2020

Eur J Clin Investigation

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Background: 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). Methods: 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 cutoffs by a ROC curve analysis in the derivation cohort as well as agreement and predictive values in the validation cohort. Results: 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 cutoff of 3.8 and 4.5.

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Section: Methodsmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Rioja

Ariza

García‐Casares

et al. 2020

Eur J Clin Investigation

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“…The remaining 10-20% of cases have bi-allelic mutations in one of four other causal genes that encode cofactors and proteins that interact with LPL, including APOC2, GPIHBP1, APOA5 and LMF1. Relatively few families worldwide with biallelic mutations in these minor genes have been reported to date [7,24,35]. Genetically defined LPL-FCS and non-LPL-FCS patients were recently shown to have very similar baseline untreated clinical and biochemical phenotypes [36].…”

Section: Genetic Diagnosismentioning

confidence: 99%

Familial chylomicronemia syndrome: an under‐recognized cause of severe hypertriglyceridaemia

et al. 2020

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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.

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“…Most recently 5 novel pathogenic mutations have been identified: 2 in LPL, 1 in GPIHBP1, and 2 in the APOA5 gene but the possibility of involvement of new genes in the manifestation of this disease cannot be excluded. 32) Extremely elevated levels of TGs cause often acute pancreatitis. Recently it has been developed a pragmatic clinical scoring, by standardizing diagnosis, which may help differentiate FHTG from multifactorial chylomicronemia syndrome (MCS), which may alleviate the need for systematic genotyping in patients with severely elevated TGs and may help identify high-priority candidates for genotyping.…”

Section: What Can Cause Elevated Concentrations Of Triglyceride-rich mentioning

confidence: 99%

Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy

Reiner

2018

Korean Circ J

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Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TGs)-rich lipoproteins as an independent risk factor has until recently been quite controversial. Recent data strongly suggest that elevated TG-rich lipoproteins are an independent risk factor for CVD and that therapeutic targeting of them could possibly provide further benefit in reducing CVD morbidity, events and mortality, apart from LDL-C lowering. Today elevated TGs are treated with lifestyle interventions, and with fibrates which could be combined with omega-3 fatty acids. There are also some new drugs. Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters. It seems that it also has some other possible antiatherogenic effects. Alipogene tiparvovec is a nonreplicating adeno-associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in treatment of the rare familial chylomicronemia syndrome.

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Molecular basis of the familial chylomicronemia syndrome in patients from the National Dyslipidemia Registry of the Spanish Atherosclerosis Society

Cited by 25 publications

References 64 publications

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

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

Familial chylomicronemia syndrome: an under‐recognized cause of severe hypertriglyceridaemia

Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy

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