A four-generation extended family tree, including consanguineous relationships, has been previously published (14). The father of both index cases 1 and 2 (see below) was affected with type 2 diabetes, dyslipidemia, and acute fatal myocardial infarction at age 69. The mother was diagnosed with type 2 diabetes, dyslipidemia, and atherosclerotic vascular disease. The carrier status of the APOA5 Q97X (the same homozygotic gene mutation found in the FCS sisters reported herein) was also confirmed in the mother and several relatives.

Female adult with a history of dyslipidemia since early childhood, previously of normal weight, and with no other relevant medical history. At age 25, she presented with an episode of acute pancreatitis during her first pregnancy, with plasma triglyceride levels reaching 3,000 mg/dL. Initial management included fibrates, niacin, and omega-3 fatty acids, along with modifications in her diet. During her second pregnancy, plasmapheresis was required due to triglyceride levels greater than 5,000 mg/dL. At age 40, she began a new treatment with fibrates, acipimox, and pravastatin, but experienced an increase in plasma creatine kinase up to 9,248 mg/dL, without presenting renal failure. Due to this increase, treatment was discontinued, but plasma triglyceride levels rose again to 5,500 mg/dL. Despite the good adherence to a low-fat diet, her plasma triglycerides remained above 500 mg/dL. At age 53, due to persistent hypertriglyceridemia and a family history of a sister with a similar diagnosis, a genetic study was performed that revealed homozygosity for the nonsense mutation Q97X of the APOA5 gene, responsible for her severe dyslipidemia. Until that time, she had not developed diabetes, arterial hypertension, or hypothyroidism.

Current treatment: At the age of 59 years, the patient began treatment with volanesorsen at a dose of 285 mg/week subcutaneously. Since the beginning of this treatment, her plasma triglyceride levels have remained below 250 mg/dL (Figure 1). She has experienced local allergic reactions with erythema and mild pruritus at the puncture site. After 3 months of treatment, the administration was adjusted to every 2 weeks. At week 16, the treatment was discontinued temporarily because the patient developed thrombocytopenia (97,000/μL). Over a follow-up period of 90 weeks, with dose of volanesorsen adjustments to 285 mg every 3 weeks, the patient has maintained plasma triglyceride levels ranging from 161 to 705 mg/dL. During this period, the patient required temporary suspension of treatment on three occasions due to platelet counts falling below 100,000/μL. Since starting treatment, she has been asymptomatic and managed adequately with dietary restriction schemes.

Female adult case with a history of dyslipidemia since early childhood. At age 30, she developed acute pancreatitis during her second pregnancy, with triglyceride levels above 9,000 mg/dL. Since then, she has been treated with a low-fat diet, avoiding refined carbohydrates and alcohol, and multiple medications, including fenofibrate, gemfibrozil, ciprofibrate, acipimox, orlistat, simvastatin, ezetimibe, niacin, and omega-3 fatty acids. In the last 10 years, plasma triglyceride levels have varied between 2,527 and 10,400 mg/dL, causing eruptive xanthomas, lipemia retinalis, and paresthesia. The patient required several hospitalizations due to abdominal pain and episodes of hypertriglyceridemia greater than 10,000 mg/dL, but without pancreatitis, where plasmapheresis has been performed, resulting in a good initial response but subsequent rise in plasma triglycerides. At 52 years of age, a genetic study was conducted that confirmed homozygosity for the nonsense mutation Q97X of the APOA5 gene, which explains her severe dyslipidemia. At 54 years of age, she was diagnosed with type 2 diabetes and began treatment with metformin and saxagliptin, followed by insulin in a basal-bolus regimen, with a glycated hemoglobin level near 6.7%. Current Treatment: The patient continues on a strict low-fat diet and multiple lipid-lowering and glucose-lowering therapies. Despite adherence to nutritional and pharmacological treatment, plasma triglyceride levels have remained poorly controlled, fluctuating between 510 and 6,360 mg/dL (mean 5,177 ± 924 mg/dL), with ongoing disease burden and recurrent healthcare utilization.

The baseline clinical and nutritional characteristics are summarized in Table 1. Dietary strategies include the following (18, 19): (a) to limit fat intake: 10–15% of the total caloric value (TCV) resulting in < 20–30 grams of fat/day for intakes of 2000 kcal/day, (b) to restrict the consumption of carbohydrates (<60% TCV), especially sugars and refined starches, (c) to consume purified medium-chain triglycerides (not transported by chylomicrons) to meet energy requirements, (d) to provide essential fatty acids (linoleic and α-linolenic; 2–4% TCV), e) to supplement fat-soluble vitamins (A, D, E, K) and micronutrients, if required, f) to avoid alcohol intake. Emphasis should be placed on the personalized application of the diet by nutritionists, providing guidance on the counting of grams of fat in foods (20). To increase adherence, culinary strategies such as buying fresh products instead of ultra-processed ones are recommended, increasing legume consumption, eliminating visible fat from the food, using alternative cooking methods (air fryers, papillote), and using spices to improve palatability (9). Unfortunately, very low-fat diets are difficult to follow, and typically have low adherence that negatively impacts long-term outcomes.

Volanesorsen is an antisense oligonucleotide drug targeting the mRNA of APO C-III, thereby promoting TG clearance through LPL-independent pathways (12). Two phase III studies have been published to evaluate volanesorsen in severe hypertriglyceridemia. The APPROACH study (21) was a randomized, double-blind, placebo-controlled clinical trial, lasting 52 weeks, conducted in 66 patients with familial chylomicronemia. This study evaluated the administration of volanesorsen (285 mg) weekly by subcutaneous injection, with 33 patients receiving volanesorsen and 33 receiving a placebo. The results showed that volanesorsen induced an 84% reduction in circulating ApoC-III levels, translating into a 77% decrease in plasma TGL levels. Among the adverse effects, 61% of patients experienced mild to moderate discomfort at the subcutaneous injection site, and 33% had decreased platelet count. The COMPASS trial (22) was a randomized, phase 3 study that compared volanesorsen therapy versus placebo in 38 patients with severe multifactorial hypertriglyceridemia or familial chylomicronemia syndrome for 26 weeks. The volanesorsen arm achieved reductions in mean plasma triglyceride concentrations of 71.2% compared to 0.9% in the placebo group. Of note, 13% of patients receiving volanesorsen developed thrombocytopenia as an adverse effect, although only one patient had a platelet count <50,000 /μL.

Phase 3 studies showed an increase in plasma LDL cholesterol levels; however, a 27–45% decrease in plasma non-HDL cholesterol levels was observed. Importantly, the volanesorsen-treated groups experienced a reduction in acute pancreatitis events compared to the placebo group. In 2019, the European Agency EMA approved the use of volanesorsen (Waylivra 285 mg(R) in adult patients with genetically confirmed FCS who are at high risk of pancreatitis and with no adequate response to diet or triglyceride-lowering therapy.