👤 Patrizia Maria Tarugi

We aimed to compare the molecular and clinical characteristics of patients identified in Italy as affected by either familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) and to assess the overall benefit of novel triglyceride-lowering therapies prescribed to these patients within the routine clinical care. From the national LIPIGEN-sHTG (Lipid Transport Disorders Italian Genetic Network-Severe Hypertriglyceridemia) registry, 169 patients (57 FCS, 51 MCS, 61 variant-negative, variant-negative MCS) were retrospectively analyzed. Data on clinical and genetic characteristics, medical history, and medications were collected. Peak triglyceride levels were used to define untreated lipid phenotypes. In FCS, 72% exhibited biallelic As compared with MCS, patients with FCS showed a more severe phenotype and higher prevalence of Show less

APOB-related familial hypobetalipoproteinemia (APOB-FHBL), the most common form of primary hypobetalipoproteinemia, often leaves heterozygous patients asymptomatic. This study aims to provide updated insights into the complications observed in heterozygous and homozygous APOB-FHBL patients. A retrospective analysis was conducted on 15 patients (53.3% female) from 7 families diagnosed with FHBL and followed in a metabolic clinic. Demographic, laboratory, clinical, and genetic data were reviewed. Patients were followed for an average of 4.5 ± 4.1 years. The median levels were as follows: low-density lipoprotein cholesterol (LDL-C; 25.7 ± 10.5 mg/dL), apolipoprotein B (ApoB; 0.3 ± 0.1 g/L), aspartate aminotransferase (AST; 40.1 ± 22.5 U/L), alanine aminotransferase (ALT; 43.0 ± 38.3 U/L), and alpha feto-protein (1.3 ± 0.7 ng/mL). Elevated AST and ALT levels were observed in 20.0% and 26.7% of cases, respectively. Vitamin E deficiency was identified in 26.7%, vitamin A deficiency in 13.3%, and vitamin D insufficiency in 66.7% of cases. Liver ultrasonography revealed hepatosteatosis in 73.3% of patients. Additionally, the study identified 5 novel APOB gene variants. Among the families, 3 had members who died due to complications related to viral infections (COVID-19, hepatitis B virus) or hepatocellular carcinoma (HCC) resulting from chronic liver disease. Patients with elevated transaminase levels or hepatosteatosis should undergo a lipid profile assessment. LDL-C levels below 50 mg/dL require further evaluation, including ApoB and fat-soluble vitamin levels. Monoallelic APOB variants are linked to poor outcomes due to deficiencies in vitamins A, E, and D, as well as an increased risk of HCC. Early recognition and regular monitoring are essential for the effective management of APOB-FHBL patients. Show less

Three members of the angiopoietin-like (ANGPTL) protein family-ANGPTL3, ANGPTL4 and ANGPTL8- are important regulators of plasma lipoproteins. They inhibit the enzyme lipoprotein lipase, which plays a key role in the intravascular lipolysis of triglycerides present in some lipoprotein classes. This review focuses on the role of ANGPTL3 as emerged from the study of genetic variants of Angptl3 gene in mice and humans. Both loss of function genetic variants and inactivation of Angptl3 gene in mice are associated with a marked reduction of plasma levels of triglyceride and cholesterol and an increased activity of lipoprotein lipase and endothelial lipase. In humans with ANGPTL3 deficiency, caused by homozygous loss of function (LOF) variants of Angptl3 gene, the levels of all plasma lipoproteins are greatly reduced. This plasma lipid disorder referred to as familial combined hypolipidemia (FHBL2) does not appear to be associated with distinct pathological manifestations. Heterozygous carriers of LOF variants have reduced plasma levels of total cholesterol and triglycerides and are at lower risk of developing atherosclerotic cardiovascular disease, as compared to non-carriers. These observations have paved the way to the development of strategies to reduce the plasma level of atherogenic lipoproteins in man by the inactivation of ANGPTL3, using either a specific monoclonal antibody or anti-sense oligonucleotides. Show less

The incidental finding of severe hypertriglyceridemia (HyperTG) in a child may suggest the diagnosis of familial chylomicronemia syndrome (FCS), a recessive disorder of the intravascular hydrolysis of triglyceride (TG)-rich lipoproteins. FCS may be due to pathogenic variants in lipoprotein lipase (LPL), as well as in other proteins, such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface) and LMF1 (a factor required for intracellular formation of active LPL). Molecular characterization of 5 subjects in whom HyperTG was an incidental finding during infancy/childhood. We performed the parallel sequencing of 20 plasma TG-related genes. Three children with severe HyperTG were found to be compound heterozygous for rare pathogenic LPL variants (2 nonsense, 3 missense, and 1 splicing variant). Another child was found to be homozygous for a nonsense variant of APOA5, which was also found in homozygous state in his father with longstanding HyperTG. The fifth patient with a less severe HyperTG was found to be heterozygous for a frameshift variant in LIPC resulting in a truncated Hepatic Lipase. In addition, 1 of the patients with LPL deficiency and the patient with APOA-V deficiency were also heterozygous carriers of a pathogenic variant in LIPC and LPL gene, respectively, whereas the patient with LIPC variant was also a carrier of a rare APOB missense variant. Targeted parallel sequencing of TG-related genes is recommended to define the molecular defect in children presenting with an incidental finding of HyperTG. Show less

Homozygous familial hypercholesterolemia is a rare clinical phenotype with a variable expression, which is characterized by extremely elevated plasma low-density lipoprotein (LDL), tendon and skin xanthomas, and a progressive atherosclerosis. In 95% of patients, homozygous familial hypercholesterolemia is due to mutations in low-density lipoprotein receptor (LDLR) gene, which abolish (receptor-negative) or greatly reduce (receptor-defective) LDLR function. The objective of the study was the molecular and phenotypic characterization of 4 siblings with severe hypercholesterolemia. The major LDL-related genes (LDLR, APOB, PCSK9, ANGPTL3, APOE, and APOC3) were sequenced. LDLR messenger RNA, isolated from leukocytes, was reverse transcribed and sequenced. The index cases were 24-year-old identical twin sisters with long-standing tendon xanthomas and high low-density lipoprotein cholesterol (LDL-C ∼10 mmol/L) but no coronary heart disease. They were carriers of 2 LDLR mutations: (1) a previously reported mutation [p.(G335S)] inherited from the mother who had LDL-C level within normal range; (2) a novel 24 bp deletion in exon 8/intron 8 junction inherited from the hypercholesterolemic (LDL-C 6.1 mmol/L) father. The deletion allele encodes an messenger RNA with a partial deletion of exon 8, whose translation product has an in-frame deletion of 17 amino acids [p.(Glu380_Gly396del)]. Family screening revealed that the 2 siblings of the twin sisters were also compound heterozygotes but had much lower LDL-C levels (8.2 and 7.1 mmol/L). The sequence of potential modifying genes showed that the 2 siblings and the mother of the twin sisters were heterozygous for a rare missense variant of apoB [p.(S2429T)], which might have an LDL-lowering effect. We report a rare event of 4 siblings found to be compound heterozygotes for 2 LDLR gene mutations but showing a different phenotype severity. The less severely affected siblings were carriers of a rare apoB missense variant. Show less

Lipase maturation factor 1 (LMF1) gene is a novel candidate gene in severe hypertriglyceridemia. Lmf1 is involved in the maturation of lipoprotein lipase (LPL) and hepatic lipase in endoplasmic reticulum. To date only one patient with severe hypertriglyceridemia and related disorders was found to be homozygous for a nonsense mutation in LMF1 gene (Y439X). The objective of the study was to investigate LMF1 gene in hypertriglyceridemic patients in whom mutations in LPL, APOC2, and APOA5 genes had been excluded. The resequencing of LMF1 gene led to the discovery of a novel homozygous nonsense mutation in one patient with severe hypertriglyceridemia and recurrent episodes of pancreatitis. The mutation causes a G>A substitution in exon 9 (c.1395G>A), leading to a premature stop codon (W464X). LPL activity and mass were reduced by 76 and 50%, respectively, compared with normolipidemic controls. The proband over the years has shown a good response to treatment. The proband's son, heterozygous for the W464X, shows normal plasma triglyceride levels. We identified the second novel pathogenic mutation in LMF1 gene in a patient with severe hypertriglyceridemia. LPL deficiency in our patient was milder than in the carrier of the Y439X previously described. Show less

In this review we compare the phenotype and lipoprotein abnormalities of some patients who were found to carry mutations in the APOA5 gene predicted to result in apolipoprotein A-V deficiency. The sequencing of the APOA5 gene in patients with primary hypertriglyceridemia, in whom mutations of the LPL and APOC2 genes had been excluded, led to the identification of four families with two different mutations in this gene predicted to result in truncated apolipoprotein A-V. The first mutation (Q148X) was found in a homozygous state in a child with severe type V hyperlipidemia, some clinical manifestations of chylomicronemia syndrome and a slight reduction in plasma postheparin lipoprotein lipase activity. Carriers of a different mutation (Q139X) were recently reported. Four Q139X heterozygotes had type V hyperlipidemia and markedly reduced plasma postheparin lipoprotein lipase activity. The hypertriglyceridemic Q139X heterozygote had other factors that could have contributed to hypertriglyceridemia. ApoB-100 kinetic studies in hypertriglyceridemic Q139X heterozygotes revealed an impairment of very low-density lipoprotein catabolism. Mutations in the APOA5 gene, leading to truncated apolipoprotein A-V devoid of lipid-binding domains located in the carboxy-terminal end of the protein, if present in the homozygous state, are expected to cause severe type V hyperlipidemia in patients with no mutations in LPL or APOC2 genes. If present in the heterozygous state, these mutations predispose to hypertriglyceridemia in combination with other genetic factors or pathological conditions. Show less

Mutations in LPL or APOC2 genes are recognized causes of inherited forms of severe hypertriglyceridemia. However, some hypertrigliceridemic patients do not have mutations in either of these genes. Because inactivation or hyperexpression of APOA5 gene, encoding apolipoprotein A-V (apoA-V), causes a marked increase or decrease of plasma triglycerides in mice, and because some common polymorphisms of this gene affect plasma triglycerides in humans, we have hypothesized that loss of function mutations in APOA5 gene might cause hypertriglyceridemia. We sequenced APOA5 gene in 10 hypertriglyceridemic patients in whom mutations in LPL and APOC2 genes had been excluded. One of them was found to be homozygous for a mutation in APOA5 gene (c.433 C>T, Q145X), predicted to generate a truncated apoA-V devoid of key functional domains. The plasma of this patient was found to activate LPL in vitro less efficiently than control plasma, thus suggesting that apoA-V might be an activator of LPL. Ten carriers of Q145X mutation were found in the patient's family; 5 of them had mild hypertriglyceridemia. As predicted from animal studies, apoA-V deficiency is associated with severe hypertriglyceridemia in humans. This observation suggests that apoA-V regulates the secretion and/or catabolism of triglyceride-rich lipoproteins. Mutations in APOA5 gene might be the cause of severe hypertriglyceridemia in subjects in whom mutations in LPL or APOC2 genes have been excluded. We detected a nonsense mutation in APOA5 gene (Q145X) in a boy with hyperchylomicronemia syndrome. This is the first observation of a complete apoA-V deficiency in humans. Show less