Autosomal Recessive Hypercholesterolemia

D’Erasmo, Laura; Minicocci, Ilenia; Nicolucci, Antonio; Pintus, Paolo; Lennep, Janine E. Roeters Van; Masana, Luís; Mata, Pedro; Sánchez-Hernández, Rosa M.; Prieto-Matos, Pablo; Real, José T.; Ascaso, Juan F.; Lafuente, Eduardo Esteve; Pocovı́, Miguel; Fuentes, Francisco; Muntoni, Sandro; Bertolini, Stefano; Sirtori, Cesare R.; Calabresi, Laura; Pavanello, Chiara; Averna, Maurizio; Cefalù, Angelo Baldassare; Noto, Davide; Pacifico, A.; Pes, Giovanni Mario; Harada‐Shiba, Mariko; Manzato, Enzo; Zambon, Sabina; Zambón, Alberto; Vogt, Anja; Scardapane, Marco; Sjouke, Barbara; Fellin, Renato; Arca, Marcello

doi:10.1016/j.jacc.2017.11.028

Cited by 45 publications

(22 citation statements)

References 25 publications

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“…SVAS is a rare nding in ARH patients with aortic stenosis (20), which is typically seen in LDLR-HoFH. In agreement with previous studies (19,21), the clinical manifestation of our ARH patient mimicked the most severe form of genetic hypercholesterolemia, LDLR-HoFH: cutaneous…”

Section: Discussionsupporting

confidence: 92%

“…However, recently the nding of a worldwide collaboration project studying 52 ARH patients (28 females, 24 males) during a mean follow-up of 14.1 ± 7.3 years showed that incidence rate of ASCVD in the treated ARH patients was comparable to the patients with HoFH (19). Another similar phenotype with LDLR-HoFH is the risk of AVS, which occurs relatively often in patients with ARH (19). SVAS is a rare nding in ARH patients with aortic stenosis (20), which is typically seen in LDLR-HoFH.…”

Section: Discussionmentioning

confidence: 96%

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An Iranian patient affected by autosomal recessive hypercholesterolemia due to a novel variant in the LDLRAP1 gene

Nikasa

Rabbani

Hejazi

et al. 2021

Preprint

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Background: Autosomal recessive hypercholesterolemia (ARH) is a rare monogenic disorder resulting from mutations of the LDLRAP1 gene, which leads to elevated LDL-C levels. Here, using whole exome sequencing (WES), we describe a 22-year-old Iranian female who carries a novel nonsense mutation in LDLRAP1. Methods: Genetic investigations were performed for the patient and her family. She showed LDL-C level of 720 mg/dL since the age of 11 years. At the age of 13 years old, aortic valve repair surgery was performed due to severe aortic valve stenosis (AVS). At the age of 17, along with prescription of rosuvastatin plus ezetimibe, coronary angiography displayed the presence of serious stenotic lesions of the coronary arteries and also aortic valve, making the patient eligible for coronary artery bypass grafting (CABG) and aortic valve replacement (AVR).Results: Genetic analysis showed the presence of a previously unreported homozygous LDLRAP1 gene variant, c.649G>T, generating a nonsense mutation at amino acid 217, shortening the ARH protein from 308 to 217 amino acid, which removes AP-2 binding domain of ARH, as an important part in LDL uptake.Conclusion: During a 10-year treatment, we observed a 74% reduction in LDL-C level. Despite the treatment with maximal dose of rosuvastatin plus ezetimibe, the results of coronary angiography demonstrated severe supravalvular aortic stenosis (SVAS) resulted in significant stenotic lesions of the coronary arteries and aortic valve. This highlights the importance of WES in early diagnosis of ARH, and it is proposed to prevent or at least delay the onset of the cardiovascular events.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 96%

An Iranian patient affected by autosomal recessive hypercholesterolemia due to a novel variant in the LDLRAP1 gene

Nikasa

Rabbani

Hejazi

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…It is caused by mutations in LDLRAP1, which codes for the low-density lipoprotein receptor adaptor protein-1. This protein plays a key role in the internalization of the LDL-R/LDL-C receptor complex, and loss-of-function mutations in the gene result in LDL-C remaining in circulation rather than being internalized by hepatocytes [37][38][39][40].…”

Section: Real-world Evidencementioning

confidence: 99%

“…Among the patients, high doses of statins and ezetimibe were recorded, and just over half of the patients were receiving apheresis. Six of the patients (11.5%) had received lomitapide [37]. Compared with other lipid lowering medication, patients receiving lomitapide had the greatest decreases in LDL-C levels, despite two of the patients stopping LA.…”

Section: Real-world Evidencementioning

confidence: 99%

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Lomitapide–a Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia

Stefanutti

2020

Curr Atheroscler Rep

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Purpose of Review Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition characterized by high levels of Low density lipoprotein cholesterol (LDL-C); overt, early-onset atherosclerotic cardiovascular disease (ASCVD); and premature cardiovascular events and mortality. Lomitapide is a first-in-class microsomal triglyceride transfer protein inhibitor for the treatment of HoFH. This review provides an update on data emerging from real-world studies of lomitapide following on from its pivotal phase 3 clinical trial in HoFH. Recent Findings Recent registry data have confirmed that HoFH is characterized by delayed diagnosis, with many patients not receiving effective therapy until they are approaching the age when major adverse cardiovascular events may occur. Data from case series of varying sizes, and from a 163-patient registry of HoFH patients receiving lomitapide, have demonstrated that lomitapide doses are lower and adverse events less severe than in the phase 3 study. Lomitapide enables many patients to reach European Atherosclerosis Society LDL-C targets. Some patients are able to reduce frequency of lipoprotein apheresis or, in some cases, stop the procedure altogether-unless there is significant elevation of lipoprotein (a). Modelling analyses based on historical and clinical trial data indicate that lomitapide has the potential to improve cardiovascular outcomes and survival in HoFH. Summary Real-world clinical experience with lomitapide has shown the drug to be effective with manageable, less marked adverse events than in formal clinical studies. Event modelling data suggest a survival benefit with lomitapide in HoFH.

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Genetic Disorders of Lipoprotein Metabolism: Diagnosis and Management

Stoekenbroek¹,

Kastelein²

2020

Clinical Cardiogenetics

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Autosomal Recessive Hypercholesterolemia

Cited by 45 publications

References 25 publications

An Iranian patient affected by autosomal recessive hypercholesterolemia due to a novel variant in the LDLRAP1 gene

An Iranian patient affected by autosomal recessive hypercholesterolemia due to a novel variant in the LDLRAP1 gene

Lomitapide–a Microsomal Triglyceride Transfer Protein Inhibitor for Homozygous Familial Hypercholesterolemia

Genetic Disorders of Lipoprotein Metabolism: Diagnosis and Management

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