0000000000133646
AUTHOR
Livia Pisciotta
Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders
Mutations in ABCA1 have been shown to be the cause of Tangier disease (TD) and some forms of familial hypoalphalipoproteinemia (HA), two genetic disorders characterized by low plasma HDL levels. Here we report six subjects with low HDL, carrying seven ABCA1 mutations, six of which are previously unreported. Two mutations (R557X and H160FsX173) were predicted to generate short truncated proteins; two mutations (E284K and Y482C) were located in the first extracellular loop and two (R1901S and Q2196H) in the C-terminal cytoplasmic domain of ABCA1. Two subjects found to be compound heterozygotes for ABCA1 mutations did not have overt clinical manifestations of TD. Three subjects, all with prema…
Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia.
Patients homozygous or Compound heterozygous for LDLR mutations or double heterozygous for LDLR and apo B R3500Q mutation have higher LDL-C levels. more extensive xanthomatosis and more severe premature coronary disease (pCAD) than simple heterozygotes for mutations in either these genes or for missense mutations in PCSK9 gene. It is not known whether combined mutations in LDLR and PKCS9 are associated with such a severe phenotype. We sequenced Apo B and PCSK9 genes in two patients with the clinical diagnosis of homozygous FH who were heterozygous for LDLR gene mutations. Proband Z.P. (LDL-C 13.39 mmol/L and pCAD) was heterozygous for an LDLR mutation (p.E228K) inherited from her father (LD…
Two Italian kindreds carrying the Arg136--Ser mutation of the Apo E gene: development of premature and severe atherosclerosis in the presence of epsilon 2 as second allele.
Abstract Background and Aims: Type III hyperlipoproteinemia, or dysbetalipoproteinemia, is commonly associated with apolipoprotein E2 homozygosity (Cy Background and Aims: 12, Cy Background and Aims: 58). Apo E2-Christchurch (Arg136→Ser), a rare mutation of the Apo E gene, located in the receptor-binding domain of the protein, has been found to be associated in the vast majority of cases of dysbetalipoproteinemia. Methods and Results: This is the first report of two Italian kindreds carrying the Arg136→Ser mutation. One family is a four-generation kindred from Genoa (Liguria, Italy) with a high rate of mortality due to coronary artery disease: the proband was a 51-year-old woman with previo…
Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features
Abstract Background and aims Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma levels of low density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease (ASCVD). HoFH is caused by pathogenic variants in several genes, such as LDLR, APOB and PCSK9, responsible for autosomal dominant hypercholesterolemia (ADH), and LDLRAP1 responsible for autosomal recessive hypercholesterolemia (ARH). Aim of this study was the review of the clinical and molecular features of patients with HoFH identified in Italy from 1989 to 2019. Methods Data were collected from lipid clinics and laboratories, …
Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia.
Background: Monogenic hypertriglyceridemia (HTG) may result from mutations in some genes which impair the intravascular lipolysis of triglyceride (TG)-rich lipoproteins mediated by the enzyme Lipoprotein lipase (LPL). Mutations in the LPL gene are the most frequent cause of monogenic HTG (familial chylomicronemia) with recessive transmission. Methods: The LPL gene was resequenced in 149 patients with severe HTG (TG>10mmol/L) and 106 patients with moderate HTG (TG>4.5 and <10mmol/L) referred to tertiary Lipid Clinics in Italy. Results: In the group of severe HTG, 26 patients (17.4%) were homozygotes, 9 patients (6%) were compound heterozygotes and 15 patients (10%) were simple heter…
Efficacy and safety of lomitapide in homozygous familial hypercholesterolaemia: the pan-European retrospective observational study
Abstract Aims Lomitapide is a lipid-lowering agent indicated as an adjunct therapy for adult homozygous familial hypercholesterolaemia (HoFH). This study evaluated the medium-term effectiveness and safety of lomitapide in a large cohort of HoFH patients in Europe. Methods and results In a multicentre retrospective, observational study including 75 HoFH patients treated with lomitapide in a real-world clinical setting from 9 European countries, low-density lipoprotein cholesterol (LDL-C) changes, adverse events (AEs), and major adverse cardiovascular events (MACE) were assessed. After a median 19 months (interquartile range 11–41 months) of treatment with a mean dosage of 20 mg of lomitapide…
Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey
Abstract Background Homozygous familial hypercholesterolemia (HoFH) is a rare life-threatening condition that represents a therapeutic challenge. The vast majority of HoFH patients fail to achieve LDL-C targets when treated with the standard protocol, which associates maximally tolerated dose of lipid-lowering medications with lipoprotein apheresis (LA). Lomitapide is an emerging therapy in HoFH, but its place in the treatment algorithm is disputed because a comparison of its long-term efficacy versus LA in reducing LDL-C burden is not available. We assessed changes in long-term LDL-C burden and goals achievement in two independent HoFH patients’ cohorts, one treated with lomitapide in Ita…
Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia
: Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause …
Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia—Brief Report
Objective— Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? Approach and Results— Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured…
Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)
Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Dat…
Additional file 1 of Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey
Additional file 1: Table 1. Patients’ genotypes. All mutations were classified according to ACMG guidelines (Chora JR, Medeiros AM, Alves AC, Bourbon M. Analysis of publicly available LDLR, APOB, and PCSK9 variants associated with familial hypercholesterolemia: application of ACMG guidelines and implications for familial hypercholesterolemia diagnosis. Genet Med. 2018;20(6):591-598). For 3 Homozygous LDLR and 1 LDLRAP1 causing mutations were not available and the diagnosis was only on clinical base. *Double Heterozygote patient for mutations in both LDLR (c.373C>T) and PCSK9 (c.60_ 65dupGCTGCT) genes.
Efficacy of Long-Term Treatment of Autosomal Recessive Hypercholesterolemia With Lomitapide: A Subanalysis of the Pan-European Lomitapide Study
Backgroundand aim: Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder of low-density lipoprotein (LDL) metabolism caused by pathogenic variants in the LDLRAP1 gene. Like homozygous familial hypercholesterolemia, ARH is resistant to conventional LDL-lowering medications and causes a high risk of atherosclerotic cardiovascular diseases (ASCVDs) and aortic valve stenosis. Lomitapide is emerging as an efficacious therapy in classical HoFH, but few data are available for ARH.Results: This is a subanalysis carried out on nine ARH patients included in the Pan-European Lomitapide Study. The age at starting lomitapide was 46 (interquartile range (IQR), 39.0–65.5) y…
Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study
Abstract Background Familial hypercholesterolemia (FH) is an autosomal dominant disease characterized by elevated plasma levels of LDL-cholesterol that confers an increased risk of premature atherosclerotic cardiovascular disease. Early identification and treatment of FH patients can improve prognosis and reduce the burden of cardiovascular mortality. Aim of this study was to perform the mutational analysis of FH patients identified through a collaboration of 20 Lipid Clinics in Italy (LIPIGEN Study). Methods We recruited 1592 individuals with a clinical diagnosis of definite or probable FH according to the Dutch Lipid Clinic Network criteria. We performed a parallel sequencing of the major…
Testing the Short-Term Efficacy of a Lipid-Lowering Nutraceutical in the Setting of Clinical Practice: A Multicenter Study
Abstract The main guidelines for cardiovascular disease prevention suggest that nutraceuticals could be an efficacious tool to improve lipid pattern. Our aim was to carry out a clinical trial comparing the metabolic effects of a combined nutraceutical containing both red yeast rice and polyunsaturated fatty acids (PUFAs) and a phytosterol-based approach in a setting of clinical practice. This was a multicenter open study with parallel control. We consecutively enrolled 107 pharmacologically untreated subjects affected by primary polygenic hypercholesterolemia and metabolic syndrome, assigned to 8-week treatment with a combined treatment with red yeast rice (Dif1Stat®, including 5 mg monacol…
Cardiac phenotype in ATP1A3-related syndromes: A multicentre cohort study
ObjectiveTo define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes.MethodsPatients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/−) to determine the sequence of events in seizure-related cardiac death.ResultsNinety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities…
Genetic polymorphisms affecting the phenotypic expression in familial hypercholesterolemia
The clinical expression of heterozygous familial hypercholesterolemia (FH) is highly variable even in patients carrying the same LDL receptor (LDL-R) gene mutation. This variability might be due to environmental factors as well as to modifying genes affecting lipoprotein metabolism. We investigated Apo E (2, 3, 4), MTP (-493G/T), Apo B (-516C/T), Apo A-V (-1131T/C), HL (-514C/T and -250G/A), FABP-2 (A54T), LPL (D9N, N291S, S447X) and ABCA1 (R219K) polymorphisms in 221 unrelated FH index cases and 349 FH relatives with defined LDL-R gene mutations. We found a significant and independent effect of the following polymorphisms on: (i) plasma LDL-C (Apo E, MTP and Apo B); (ii) plasma HDL-C (HL, …
Mutations in MTP gene in abeta- and hypobeta-lipoproteinemia.
Abstract Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are inherited disorders of apolipoprotein B (apo B)-containing lipoproteins that result from mutations in apo B and microsomal triglyceride transfer protein (MTP) genes, respectively. Here we report three patients with severe deficiency of plasma low-density lipoprotein (LDL) and apo B. Two of them (probands F.A. and P.E.) had clinical and biochemical phenotype consistent with ABL. Proband F.A. was homozygous for a minute deletion/insertion (c.1228delCCCinsT) in exon 9 of MTP gene predicted to cause a truncated MTP protein of 412 amino acids. Proband P. E. was heterozygous for a mutation in intron 9 (IVS9-1G>A),…
CLINICAL CHARACTERISTICS AND PLASMA LIPIDS IN SUBJECTS WITH FAMILIAL COMBINED HYPOLIPIDEMIA: A POOLED ANALYSIS
Background. Angiopoietin-like 3 (ANGPTL3) regulates lipoprotein metabolism by modulating extracellular lipases. Loss-of function mutations in ANGPTL3 gene cause familial combined hypolipidemia (FHBL2). The mode of inheritance and hepatic and vascular consequences of FHBL2 have not been fully elucidated. To get further insights on these aspects, we re-evaluated the clinical and the biochemical characteristics of all reported cases of FHBL2. Methods and Results. One hundred fteen FHBL2 individuals carrying 13 different mutations in the ANGPTL3 gene (14 homozygotes, 8 compound heterozygotes and 93 heterozygotes) and 402 controls were considered. Carriers of 2 mutant alleles had undetectable pl…
Familial hypercholesterolemia: The Italian Atherosclerosis Society Network (LIPIGEN)
Background and aims: Primary dyslipidemias are a heterogeneous group of disorders characterized by abnormal levels of circulating lipoproteins. Among them, familial hypercholesterolemia is the most common lipid disorder that predisposes for premature cardiovascular disease. We set up an Italian nationwide network aimed at facilitating the clinical and genetic diagnosis of genetic dyslipidemias named LIPIGEN (LIpid TransPort Disorders Italian GEnetic Network). Methods: Observational, multicenter, retrospective and prospective study involving about 40 Italian clinical centers. Genetic testing of the appropriate candidate genes at one of six molecular diagnostic laboratories serving as nationw…
Worldwide experience of homozygous familial hypercholesterolaemia:retrospective cohort study
[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally.
Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.
Abstract Objective To determine the spectrum of gene mutations and the genotype–phenotype correlations in patients with Autosomal Dominant Hypercholesterolemia (ADH) identified in Italy. Methods The resequencing of LDLR , PCSK9 genes and a selected region of APOB gene were conducted in 1018 index subjects clinically heterozygous ADH and in 52 patients clinically homozygous ADH. The analysis was also extended to 1008 family members of mutation positive subjects. Results Mutations were detected in 832 individuals: 97.4% with LDLR mutations, 2.2% with APOB mutations and 0.36% with PCSK9 mutations. Among the patients with homozygous ADH, 51 were carriers of LDLR mutations and one was an LDLR / …
Additional file 2 of Long-term efficacy of lipoprotein apheresis and lomitapide in the treatment of homozygous familial hypercholesterolemia (HoFH): a cross-national retrospective survey
Additional file 2: Figure 1. LDL-C burden according to lomitapide or LA treatment. A Box plot graphs represent the median values of cumulative LDL-C burden in the Lomitapide cohort (dark grey) and in the LA cohort (light grey). For the total LDL-C burden calculation see Methods. P values are adjusted for age at follow-up, untreated LDL-C values and gender. B, C Box plot graphs represent the median values of TC and LDL-C burden at baseline and on-treatment. For baseline and on-treatment TC or LDL-C burden calculation see Methods. Δ% represents TC and LDL-c percent reduction from baseline and is reported with the respective statistical significance. B shows data form Lomitapide cohort whereas…