Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features

Bertolini, Stefano; Calandra, Sebastiano; Arca, Marcello; Averna, Maurizio; Catapano, Alberico L.; Tarugi, Patrizia; Bartuli, Andrea; Bucci, Marco; Buonuomo, Paola Sabrina; Calabrò, Paolo; Casula, Manuela; Cefalù, Angelo Baldassare; Cicero, A.F.G.; D’Addato, Sergio; D’Erasmo, Laura; Fasano, Tommaso; Iannuzzo, Gabriella; Ibba, Anastasia; Negri, Emanuele Alberto; Pasta, Andrea; Pavanello, Chiara; Rabacchi, Claudio; Ripoli, Carlo; Sampietro, Tiziana; Sbrana, Francesco; Sileo, Fulvio; Suppressa, Patrizia; Trenti, Chiara; Zenti, Maria Grazia

doi:10.1016/j.atherosclerosis.2020.08.027

Cited by 28 publications

(37 citation statements)

References 38 publications

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“…Less frequently, HoFH phenotype is caused by biallelic mutations in other two genes that also regulate plasma clearance of LDL: the APOB gene and the PCSK9 gene. The first one encodes for apolipoprotein B (apoB), the structural protein of the LDL particle, whereas the second one synthesizes the circulatory protease proprotein convertase subtilisin/kexin type 9 (PCSK9) which is able to limit the LDLR membrane recycling [4]. In addition, HoFH may also recognize a recessive pattern of inheritance, the so-called autosomal recessive hypercholesterolemia (ARH), which is due to mutations in the adaptor protein, LDLRAP1.…”

Section: Introductionmentioning

confidence: 99%

“…This protein is pivotal in normally orienting the LDLR on the cell surface as well as in allowing the efficient internalization of the LDLR-LDL particle complex [5]. Independently from the mechanism, the HoFH phenotype is characterized by a seriously impaired removal of LDL particles that massively accumulates in plasma, thus leading to marked elevation of LDL-C and acceleration of atherosclerosis processes [4]. Indeed, HoFH patients have levels of LDL-C around 13.0 mmol/L (~500 mg/dL) since birth and cardiovascular events occurring at a mean age of 12.5 years [3].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, HoFH patients have levels of LDL-C around 13.0 mmol/L (~500 mg/dL) since birth and cardiovascular events occurring at a mean age of 12.5 years [3]. It has been demonstrated that risk of atherosclerotic cardiovascular disease (ASCVD) events in HoFH is dependent on the LDL burden, as can be estimated by the cholesterol-year score [4]. This, in turn, relates to the severity of LDLR dysfunction and genotypes [4].…”

Section: Introductionmentioning

confidence: 99%

“…It has been demonstrated that risk of atherosclerotic cardiovascular disease (ASCVD) events in HoFH is dependent on the LDL burden, as can be estimated by the cholesterol-year score [4]. This, in turn, relates to the severity of LDLR dysfunction and genotypes [4]. In a recent Italian survey, HoFH patients who are genotypically true homozygotes showed a more severe LDL-C phenotype and increased frequencies of cardiovascular events than those who are compound heterozygotes [4,6].…”

Section: Introductionmentioning

confidence: 99%

“…This, in turn, relates to the severity of LDLR dysfunction and genotypes [4]. In a recent Italian survey, HoFH patients who are genotypically true homozygotes showed a more severe LDL-C phenotype and increased frequencies of cardiovascular events than those who are compound heterozygotes [4,6]. Moreover, carriers of LDLR null variants presented with a more aggressive phenotype as compared to carriers of LDLR defective variants.…”

Section: Introductionmentioning

confidence: 99%

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Rare Treatments for Rare Dyslipidemias: New Perspectives in the Treatment of Homozygous Familial Hypercholesterolemia (HoFH) and Familial Chylomicronemia Syndrome (FCS)

D’Erasmo

Bini

Arca

2021

Curr Atheroscler Rep

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Purpose of Review This review aims to summarize the most recent published literature concerning lomitapide and volanesorsen that are approved for the use in HoFH and FCS patients, respectively. Moreover, it will briefly revise the published evidence on novel, non-approved treatments that are under evaluation for the management of these rare forms of dyslipidemias Recent Findings The definition of rare dyslipidemias identifies a large number of severe disorders of lipid metabolism of genetic origin. Among them were homozygous familial hypercholesterolemia (HoFH) (OMIM #143890) and familial chylomicronemia syndrome (FCS) (OMIM #238600), which are characterized by a markedly impaired cholesterol- and triglyceride-containing lipoproteins metabolism. They are being particularly associated with poor health outcomes and quality of life. Considering the severity of these diseases, common lipid-lowering drugs are often ineffective or do not allow to achieve the recommended lipid targets to prevent the development of complications. Nowadays, several new drugs have been found to effectively treat HoFH and FCS with an acceptable safety profile. Summary Treating patients with HoFH and FCS remains very challenging. However, novel treatment options are emerging and might be considered in addition to conventional therapy for managing these diseases. These novel drugs will possibly change the natural history of these two rare and life-threatening diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rare Treatments for Rare Dyslipidemias: New Perspectives in the Treatment of Homozygous Familial Hypercholesterolemia (HoFH) and Familial Chylomicronemia Syndrome (FCS)

D’Erasmo

Bini

Arca

2021

Curr Atheroscler Rep

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Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia

Mulder,

Tromp,

Al-Khnifsawi

et al. 2024

JAMA Cardiol

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ImportanceHomozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely increased low-density lipoprotein (LDL) cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous familial hypercholesterolemia (HeFH) is more common than HoFH, and women with HeFH are diagnosed later and undertreated compared to men; it is unknown whether these sex differences also apply to HoFH.ObjectiveTo investigate sex differences in age at diagnosis, risk factors, lipid-lowering treatment, and ASCVD morbidity and mortality in patients with HoFH.Design, Setting, and ParticipantsSex-specific analyses for this retrospective cohort study were performed using data from the HoFH International Clinical Collaborators (HICC) registry, the largest global dataset of patients with HoFH, spanning 88 institutions across 38 countries. Patients with HoFH who were alive during or after 2010 were eligible for inclusion. Data entry occurred between February 2016 and December 2020. Data were analyzed from June 2022 to June 2023.Main Outcomes and MeasuresComparison between women and men with HoFH regarding age at diagnosis, presence of risk factors, lipid-lowering treatment, prevalence, and onset and incidence of ASCVD morbidity (myocardial infarction [MI], aortic stenosis, and combined ASCVD outcomes) and mortality.ResultsData from 389 women and 362 men with HoFH from 38 countries were included. Women and men had similar age at diagnosis (median [IQR], 13 [6-26] years vs 11 [5-27] years, respectively), untreated LDL cholesterol levels (mean [SD], 579 [203] vs 596 [186] mg/dL, respectively), and cardiovascular risk factor prevalence, except smoking (38 of 266 women [14.3%] vs 59 of 217 men [27.2%], respectively). Prevalence of MI was lower in women (31 of 389 [8.0%]) than men (59 of 362 [16.3%]), but age at first MI was similar (mean [SD], 39 [13] years in women vs 38 [13] years in men). Treated LDL cholesterol levels and lipid-lowering therapy were similar in both sexes, in particular statins (248 of 276 women [89.9%] vs 235 of 258 men [91.1%]) and lipoprotein apheresis (115 of 317 women [36.3%] vs 118 of 304 men [38.8%]). Sixteen years after HoFH diagnosis, women had statistically significant lower cumulative incidence of MI (5.0% in women vs 13.7% in men; subdistribution hazard ratio [SHR], 0.37; 95% CI, 0.21-0.66) and nonsignificantly lower all-cause mortality (3.0% in women vs 4.1% in men; HR, 0.76; 95% CI, 0.40-1.45) and cardiovascular mortality (2.6% in women vs 4.1% in men; SHR, 0.87; 95% CI, 0.44-1.75).Conclusions and RelevanceIn this cohort study of individuals with known HoFH, MI was higher in men compared with women yet age at diagnosis and at first ASCVD event were similar. These findings suggest that early diagnosis and treatment are important in attenuating the excessive cardiovascular risk in both sexes.

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Correspondence on: “Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features”

Biesecker

2021

Atherosclerosis

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Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features

Cited by 28 publications

References 38 publications

Rare Treatments for Rare Dyslipidemias: New Perspectives in the Treatment of Homozygous Familial Hypercholesterolemia (HoFH) and Familial Chylomicronemia Syndrome (FCS)

Rare Treatments for Rare Dyslipidemias: New Perspectives in the Treatment of Homozygous Familial Hypercholesterolemia (HoFH) and Familial Chylomicronemia Syndrome (FCS)

Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia

Correspondence on: “Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features”

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