👤 Ovidio Muñiz-Grijalvo

Severe hypertriglyceridemia (fasting triglycerides >500 mg/dL) is an uncommon and heterogeneous condition in children. The aim of this work was to assess the etiology of severe hypertriglyceridemia seen in 8 pediatric patients. Eight pediatric cases with severe hypertriglyceridemia underwent clinical, biochemical, and genetic evaluations. The laboratory tests performed included lipoprotein separation by ultracentrifugation and measurement of their lipid content, measurement of apolipoproteins, analyses of post-heparin plasma lipoprotein lipase (LPL) activity and mass, detection of autoantibodies against GPIHBP1, and targeted next-generation sequencing. All children (3-16 years) had recorded fasting serum triglyceride levels >800 mg/dL (9 mmol/L) at least once. Five cases with pathogenic or likely pathogenic biallelic variants in GPIHBP1 (2 cases), APOA5 (1 case), APOC2 (1 case), and LPL (1 case) were diagnosed with familial chylomicronemia syndrome based on their clinical, biochemical, and genetic features. Additionally, 1 child had autoimmune chylomicronemia due to the presence of autoantibodies against GPIHBP1. Finally, 2 patients had severe hypertriglyceridemia due to secondary causes: 1 girl with the onset of type 1 diabetes in the context of diabetic ketoacidosis, and the other patient due to total parenteral nutrition and low-molecular-weight heparin. The etiology of severe hypertriglyceridemia in children is heterogeneous. A multidisciplinary approach helps to reach a definitive diagnosis and, therefore, to recommend specific therapy. Show less

Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases. 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients. Twenty-four biallelic variants were analyzed. Evidence-based criteria allowed the reclassification of 8 likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of 2 variants of uncertain significance (VUS) to LP. Conversely, 2 variations in LMF1 remained as VUS. Additionally, 1 variant in LPL and 2 in GPIHBP1 were likely benign. Twenty FCS cases had biallelic P/LP variants and 1 patient, with an FCS phenotype, harbored biallelic VUS. FCS was excluded from 4 patients with pathogenic/likely benign combinations. The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases. Show less

The development of massive sequencing techniques and guidelines for assessing the pathogenicity of variants are allowing us the identification of new cases of familial chylomicronemia syndrome (FCS) mostly in the LPL gene, less frequently in GPIHBP1 and APOA5, and with even fewer cases in LMF1 and APOC2. From the included studies, it can be deduced that, in cases with multifactorial chylomicronemia syndrome (MCS), both loss-of-function variants and common variants in canonical genes for FCH contribute to the manifestation of this other form of chylomicronemia. Other common and rare variants in other triglyceride metabolism genes have been identified in MCS patients, although their real impact on the development of severe hypertriglyceridemia is unknown. There may be up to 60 genes involved in triglyceride metabolism, so there is still a long way to go to know whether other genes not discussed in this monograph (MLXIPL, PLTP, TRIB1, PPAR alpha or USF1, for example) are genetic determinants of severe hypertriglyceridemia that need to be taken into account. Show less

Familial chylomicronemia syndrome (FCS) is a very rare, underdiagnosed disorder that can cause abdominal pain and recurrent pancreatitis from childhood -potentially life-threatening- and chronic complications such as diabetes mellitus and exocrine pancreatic insufficiency. FCS affects the quality of life and mental health of those who suffer from it, aspects that must be taken into account in its treatment, based on a strict low-fat diet, which is difficult to adhere to and persist. People with FCS lack the lipolytic capacity to hydrolyze triglycerides (TG) and have a minimal or null response to conventional lipid-lowering treatments. ApoCIII antagonists, specifically volanesorsen, olezarsen and ARO-APOC3, are the most promising drugs to reduce TG concentrations in patients with FCS. Anti-ANGPTL3 therapies appear to be less effective. More clinical trials and new pharmacological treatments are needed to improve the quality of life and prognosis of people with FCS. Show less

Familial chylomicronemia syndrome (FCS) is an extremely rare lipoprotein disorder caused by mutations in at least 5 genes of the lipoprotein lipase (LPL) complex. This work shows the molecular analysis of patients diagnosed with FCS, who attended the Spanish Arteriosclerosis Society lipid units and were included in the National Dyslipidemia Registry. Among the 238 patients registered with severe hypertriglyceridemia (fasting triglycerides >1000 mg/dL), 26 were diagnosed with FCS as they had confirmed postheparin plasma LPL activity deficiency and/or homozygosity for loss-of-function mutations in LPL, GPIHBP1, APOC2, LMF1, or Apolipoprotein A5 (APOA5). Among the 26 FCS cases, 23 had mutations in the homozygous state: 19 in LPL and 4 in the GPIHBP1 gene. The molecular analysis revealed 3 novel mutations: 2 in LPL, in 2 unrelated patients (c.312delA; p.Asp105Thrfs*66 and c.629A>G; p.His210Arg), and 1 in GPHIBP1 in a third patient (c.502delC; p.Leu168Serfs*83). These 3 patients had confirmed lack of LPL activity. Three additional patients with confirmed LPL activity deficiency were heterozygous carriers of mutations in the genes analyzed. Among these, we found 2 novel mutations in APOA5 (c.50-1G>A and c.326₃₂₇insC; p.Tyr110Leufs*158). We have identified 5 novel pathogenic mutations: 2 in LPL, 1 in GPIHBP1, and 2 in the APOA5 gene. The genetic defaults accounting for the LPL activity deficiency of 23 of them have been clearly identified and 3 patients, who harbored mutations in heterozygosity, were diagnosed based on LPL activity deficiency, which raises the question of the involvement of new genes in the manifestation of FCS. Show less