原発性高カイロミクロン血症

INTRODUCTION: The National Dyslipidemia Registry of the Spanish Atherosclerosis Society (SEA) represents a major source of real-world evidence on lipid metabolism disorders in Spain. This study aims to describe the evolution of the registry, its main scientific contributions, and its current role in the development of precision medicine strategies. METHODS: A descriptive study was conducted based on the analysis of the SEA National Dyslipidemia Registry, complemented by a structured review of the main scientific publications derived from it. Studies related to familial hypercholesterolemia, rare dyslipidemias, response to lipid-lowering therapy, artificial intelligence, and lipoprotein(a) were included. Updated data on the number of patients and participating centers were also incorporated. RESULTS: As of March 2026, the registry includes 10,073 patients from 113 lipid units across Spain. The studies derived from the registry have enabled a detailed characterization of the clinical and genetic profile of familial hypercholesterolemia, identified a significant gap in lipid control in routine clinical practice, and demonstrated substantial variability in response to lipid-lowering therapy. In addition, the role of lipoprotein(a) as an independent cardiovascular risk factor has been further elucidated, including its interaction with other lipid parameters and sex-related differences. The registry has also improved the characterization of rare dyslipidemias, such as familial chylomicronemia syndrome and homozygous familial hypercholesterolemia. The incorporation of artificial intelligence models has enhanced cardiovascular risk stratification. CONCLUSIONS: The SEA National Dyslipidemia Registry has become a reference platform for cardiovascular research in real-world settings, supporting the transition toward precision medicine through the integration of clinical, genetic, and analytical data.

Severe hypertriglyceridemia (triglycerides ≥ 500 mg/dL) carries a high risk of recurrent acute pancreatitis and cardiovascular disease. Pathogenic variants in the APOA5 gene are associated with hyperlipoproteinemia type V and familial hypertriglyceridemia; however, detailed case reports involving variants of uncertain significance (VUS) with a severe clinical phenotype and documented therapeutic response are rarely published. A 46-year-old woman from rural Supía, Caldas, Colombia, presented with persistent very severe hypertriglyceridemia (peak: 2,170 mg/dL), three hospitalizations for acute pancreatitis, and inadequate response to statins and fibrates. Targeted exome sequencing identified a heterozygous APOA5 VUS: c.694T>C, p.Ser232Pro (NM_052968.5), classified as PM2/PP3 per ACMG criteria (ClinVar: VCV002617654.3). An off-label PCSK9 inhibitor regimen achieved a greater than 90% triglyceride reduction (nadir: 118 mg/dL), though adherence has been intermittent due to economic and healthcare access barriers. This case highlights the diagnostic value of targeted genetic testing in severe familial hypertriglyceridemia and illustrates how an APOA5 VUS may underlie a severe multifactorial chylomicronemia phenotype. Segregation analysis and functional studies in first-degree relatives are warranted to support variant reclassification. This report also underscores the impact of healthcare access barriers on rare metabolic disease outcomes in rural Latin America.

Hypertriglyceridemia is a prevalent lipid disorder associated with residual atherosclerotic cardiovascular disease (ASCVD) risk and increased risk of acute pancreatitis at triglyceride (TG) levels above 1000 mg/dL. Causes of hypertriglyceridemia are multifactorial and may be a result of secondary causes (Western diet, alcohol, medications, uncontrolled diseases/disorders), genetic disorders, or a combination of both. Two novel medications (olezarsen, plozasiran), which inhibit hepatic production of apoC-III mRNA and increase TG clearance, have recently been approved to reduce TG levels in adults with familial chylomicronemia syndrome (FCS). Both olezarsen and plozasiran have been evaluated in randomized, placebo-controlled, clinical trials in patients with varying degrees of hypertriglyceridemia. In this review, we report the lipid-lowering effects and safety of both olezarsen and plozasiran from clinical trials in patients with hypertriglyceridemia. Based on available data, both agents are associated with significant TG-lowering effects via reductions in apoC-III, as well as favorable effects on other lipid parameters. Overall, both agents appear generally well tolerated, although monitoring of liver enzymes and glycemic control is warranted for both agents, and additional monitoring of platelet counts for olezarsen. Future clinical trials are needed to assess whether the TG-lowering effects of each agent are associated with reduced risk of pancreatitis and ASCVD events.

Severe hypertriglyceridemia (sHTG) is a critical metabolic disorder that substantially elevates the risk of atherosclerotic vascular disease and acute pancreatitis. Despite its clinical significance, many conventional triglyceride-lowering therapies often fail to adequately reduce triglyceride levels or prevent these life-threatening complications. This unmet need has spurred interest in targeting regulatory proteins involved in triglyceride metabolism, such as apolipoprotein C3 (apoC-III), a key inhibitor of lipoprotein lipase activity that promotes triglyceride-rich lipoprotein (TRL) accumulation. Plozasiran, an investigational small interfering RNA (siRNA) therapy, has emerged as a breakthrough in sHTG management by selectively degrading hepatic APOC3 mRNA. Indeed, clinical trials demonstrate this drug's robust efficacy in reducing triglyceride levels, concomitant with reduced non-HDL cholesterol and apolipoprotein B-key markers of cardiovascular risk. Notably, the Phase III PALISADE trial in familial chylomicronemia syndrome patients revealed plozasiran's potential to mitigate acute pancreatitis risk by normalizing triglyceride levels with a favorable safety profile. Current guidelines emphasize a multimodal approach to sHTG, combining dietary restriction of fats and simple carbohydrates with pharmacotherapy. However, plozasiran's prolonged dosing interval and mechanism-based action position it as a transformative option, particularly for patients refractory to existing treatments. While long-term cardiovascular outcome data remain pending, its ability to durably modulate APOC3 expression offers new hope for breaking the cycle of dyslipidemia-driven organ damage. As research progresses, this therapy may redefine standards of care for high-risk populations, bridging a critical gap in preventive cardiology and pancreatology.

BACKGROUND: Lipoprotein lipase (LPL) is essential for plasma triglyceride (TG) hydrolysis, and biallelic LPL loss-of-function variants cause familial chylomicronemia syndrome. However, the clinical and functional significance of heterozygous LPL variants remains incompletely characterized. We investigated two heterozygous LPL missense variants, c.1187A>T (p.Glu396Val) and the novel c.1251G>C (p.Trp417Cys), in patients with severe hypertriglyceridemia (HTG). METHODS: Two probands underwent comprehensive clinical, biochemical, and imaging assessments. Genetic analysis involved whole-exome sequencing and Sanger confirmation. Variant interpretation incorporated in silico prediction, evolutionary conservation, AlphaFold-based residue mapping, LPL-GPIHBP1 structural-context analysis, and NetCGlyc prediction. Functional effects were assessed in HEK293T cells transfected with wild-type or mutant LPL plasmids, measuring mRNA/protein expression and enzymatic activity. RESULTS: Clinically, Proband 1 exhibited recurrent pancreatitis with moderate hyperglycemia, whereas Proband 2 had extreme HTG without pancreatitis but with severe insulin resistance, reflecting variable expressivity. Two LPL missense variants, c.1187A>T (p.Glu396Val) and the novel c.1251G>C (p.Trp417Cys), both located in exon 8. Both affected residues were highly conserved and localized to the C-terminal domain by AlphaFold-based mapping. NetCGlyc predicted Trp417 as a potential C-mannosylation-related residue. Mutant LPL mRNA and protein expression were comparable to wild-type, whereas enzymatic activity was significantly reduced in cell lysates and culture medium. CONCLUSIONS: These findings provide functional evidence that p.Glu396Val and the novel p.Trp417Cys impair LPL enzymatic activity despite preserved protein abundance, supporting a qualitative functional defect. Our findings highlight the value of functional validation and metabolic assessment in interpreting heterozygous LPL variants in HTG.