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

Biesecker, Leslie G.

doi:10.1016/j.atherosclerosis.2021.03.015

Cited by 4 publications

(3 citation statements)

References 3 publications

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“…21 More recently, a rare autosomal recessive form of FH [autosomal recessive hypercholesterolaemia (ARH)] accounting for <1% of cases was identified, caused by bi-allelic loss-of-function variants in LDLRAP1 (see abbreviations in Box 2); heterozygotes are true 'carriers': with normal LDL-C levels. 22 As an autosomal semi-dominant condition, 23 individuals with one copy of a pathogenic DNA variant-i.e. mono-allelic or heterozygous FH (HeFH)-express an abnormal biochemical phenotype, sometimes with characteristic clinical features.…”

Section: Genetic Criteria and Interpreting Genetic Test Resultsmentioning

confidence: 99%

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance

FJ,

et al. 2023

ESPE

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Homozygous familial hypercholesterolaemia is a rare autosomal semi-dominant disease affecting males and females equally, characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) from conception and accelerated atherosclerotic cardiovascular disease, often resulting in early death. Homozygous familial hypercholesterolaemia is diagnosed late and undertreated; both established and novel therapies offer hope to patients, but treatment inequity exacerbates poorer outcomes in less affluent countries. 12 APOB, apolipoprotein B gene; CI, confidence interval; HR, hazard ratio; LDLR, low-density lipoprotein receptor gene; LDLRAP1, low-density lipoprotein adaptor protein 1 gene; PCSK9, proprotein conertase subtilisin/kexin type 9 gene.

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Section: Genetic Criteria and Interpreting Genetic Test Resultsmentioning

confidence: 99%

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance

FJ,

et al. 2023

ESPE

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“…A unique molecular event that probably occurred in the past in the E4 allele was transmitted through generations and is now reported as “ApoE4 Freiburg” [ 24 ]. The homozygote ApoE4 Freiburg carrier did not present a more severe phenotype ( Table 1 ); thus, the transmission mode seemed to be dominant rather than semi-dominant [ 25 ]. The p.Arg163Cys variant that was previously reported in a French ADH family and two probands [ 10 ] was carried by one ADH subject who suffered from myocardial infarction at 40 years old and two FCHL subjects ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia

Abou-Khalil

Marmontel

Ferrières

et al. 2022

IJMS

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Primary hypercholesterolemia is characterized by elevated LDL-cholesterol (LDL-C) levels isolated in autosomal dominant hypercholesterolemia (ADH) or associated with elevated triglyceride levels in familial combined hyperlipidemia (FCHL). Rare APOE variants are known in ADH and FCHL. We explored the APOE molecular spectrum in a French ADH/FCHL cohort of 5743 unrelated probands. The sequencing of LDLR, PCSK9, APOB, and APOE revealed 76 carriers of a rare APOE variant, with no mutation in LDLR, PCSK9, or APOB. Among the 31 APOE variants identified here, 15 are described in ADH, 10 in FCHL, and 6 in both probands. Five were previously reported with dyslipidemia and 26 are novel, including 12 missense, 5 synonymous, 2 intronic, and 7 variants in regulatory regions. Sixteen variants were predicted as pathogenic or likely pathogenic, and their carriers had significantly lower polygenic risk scores (wPRS) than carriers of predicted benign variants. We observed no correlation between LDL-C levels and wPRS, suggesting a major effect of APOE variants. Carriers of p.Leu167del were associated with a severe phenotype. The analysis of 11 probands suggests that carriers of an APOE variant respond better to statins than carriers of a LDLR mutation. Altogether, we show that the APOE variants account for a significant contribution to ADH and FCHL.

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“…In these conditions, of which FH is the most familiar example ( 130 ), individuals with a single monoallelic variant (ie, heterozygotes) have a less severe phenotype than individuals with biallelic variants. In the past, this additive effect was described using the term “codominant” inheritance, but now the newer term “semidominant” or “incomplete dominant” has been proposed for FH ( 131 ). In semidominant inheritance, heterozygotes display an abnormal biochemical phenotype sometimes with characteristic clinical features ( Table 5 ).…”

Section: Rare Dyslipidemiasmentioning

confidence: 99%

A Modern Approach to Dyslipidemia

2021

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Lipid disorders involving derangements in serum cholesterol, triglycerides or both are commonly encountered in clinical practice and often have implications for cardiovascular risk and overall health. Recent advances in knowledge, recommendations and treatment options have necessitated an updated approach to these disorders. Older classification schemes have outlived their usefulness yielding to an approach based on the primary lipid disturbance identified on a routine lipid panel as a practical starting point. While monogenic dyslipidemias exist and are important to identify, most individuals with lipid disorders have polygenic predisposition, often in the context of secondary factors such as obesity and type 2 diabetes. With regard to cardiovascular disease, elevated low density lipoprotein cholesterol is essentially causal and clinical practice guidelines worldwide have recommended treatment thresholds and targets for this variable. Furthermore, recent studies have established elevated triglycerides as a cardiovascular risk factor, while depressed high density lipoprotein cholesterol now appears less contributory than was previously believed. An updated approach to diagnosis and risk assessment may include measurement of secondary lipid variables such as apolipoprotein B and Lipoprotein(a), together with selective use of genetic testing to diagnose rare monogenic dyslipidemias such as familial hypercholesterolemia or familial chylomicronemia syndrome. The ongoing development of new agents – especially antisense RNA and monoclonal antibodies - targeting dyslipidemias will provide additional management options, which in turn motivates discussion on how best to incorporate them into current treatment algorithms.

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

Cited by 4 publications

References 3 publications

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance

APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia

A Modern Approach to Dyslipidemia

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