Familial dysbetalipoproteinemia: an underdiagnosed lipid disorder

Koopal, Charlotte; Ad, Marais; Visseren, Frank L.J.

doi:10.1097/med.0000000000000316

Cited by 67 publications

(21 citation statements)

References 51 publications

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“…1-5 Apolipoprotein (apo) E is a component of chylomicrons and their remnants, very low-density lipoprotein (VLDL), and intermediate density lipoprotein (IDL). 1-5 Apo E mediates clearance of these lipoproteins and also plays an independent role in lipid metabolism in the brain. 6 Three common isoforms of apo E, namely, E4, E3, and E2, differ by single amino acid changes encoded by common polymorphisms within the APOE gene.…”

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confidence: 99%

“…5 The cysteine at residue 176 in E2 leads to reduced binding affinity for cell surface receptors compared with E3. 2-5 E2 allele frequency is ~10%, so that ~1% of people are homozygous for E2/E2. Because only ~10% of E2/E2 homozygotes develop FDBL, 2-5 a second “hit” such as obesity, hypothyroidism, renal disease, estrogen deficiency, diabetes, or another genetic mutation is required for clinical expression.…”

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confidence: 99%

“…2-5 E2 allele frequency is ~10%, so that ~1% of people are homozygous for E2/E2. Because only ~10% of E2/E2 homozygotes develop FDBL, 2-5 a second “hit” such as obesity, hypothyroidism, renal disease, estrogen deficiency, diabetes, or another genetic mutation is required for clinical expression. 2-5 Occasionally, extremely rare missense mutations or deletion-duplication variants that impact on other amino acid residues of apo E can lead to compromised protein function, presenting clinically as FDBL.…”

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confidence: 99%

“…2-5 Occasionally, extremely rare missense mutations or deletion-duplication variants that impact on other amino acid residues of apo E can lead to compromised protein function, presenting clinically as FDBL. 2-5…”

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confidence: 99%

“…Clinical features of FDBL include tuberous and palmar xanthoma, plus increased risk of premature coronary and peripheral artery disease. 2-5 Patients classically show equimolar elevations in serum total cholesterol (TC) and triglyceride (TG), 2-5 due to massively elevated IDL. IDL is a normally a minor lipoprotein fraction but it accumulates in FDBL patients due to compromised particle binding from E2/E2 homozygosity.…”

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confidence: 99%

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Severe Combined Dyslipidemia With a Complex Genetic Basis

Abbas

McIntyre

et al. 2019

Journal of Investigative Medicine High Impact Case Reports

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Background. Familial dysbetalipoproteinemia (also known as type 3 hyperlipoproteinemia) is typically associated with homozygosity for the apolipoprotein E2 isoform, but also sometimes with dominant rare missense variants in the APOE gene. Patients present with roughly equimolar elevations of cholesterol and triglyceride (TG) due to pathologic accumulation of remnant lipoprotein particles. Clinical features include tuberoeruptive xanthomas, palmar xanthomas, and premature vascular disease. Case. A 48-year-old male presented with severe combined dyslipidemia: total cholesterol and TG were 11.5 and 21.4 mmol/L, respectively. He had dyslipidemia since his early 20s, with tuberous xanthomas on his elbows and knees. His body mass index was 42 kg/m2. He also had treated hypertension, mild renal impairment, and a history of gout. He had no history of cardiovascular disease, peripheral arterial disease, or pancreatitis. Multiple medications had been advised including rosuvastatin, ezetimibe, fenofibrate, and alirocumab, but his lipid levels were never adequately controlled. Genetic Analysis. Targeted next-generation sequencing identified (1) the APOE E2/E2 homozygous genotype classically described with familial dysbetalipoproteinemia; (2) in addition, one APOE E2 allele contained the rare heterozygous missense variant p.G145D, previously termed apo E-Bethesda; (3) a rare heterozygous APOC2 nonsense variant p.Q92X; and (4) a high polygenic risk score for TG levels (16 out of 28 TG-raising alleles) at the 82nd percentile for age and sex. Conclusion. The multiple genetic “hits” on top of the classical APOE E2/E2 genotype likely explain the more severe dyslipidemia and refractory clinical phenotype.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Severe Combined Dyslipidemia With a Complex Genetic Basis

Abbas

McIntyre

et al. 2019

Journal of Investigative Medicine High Impact Case Reports

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Clinical Lipidology and the Prevention of Vascular Disease: Time for Personalized Therapy

Brown

2018

Clin Pharma and Therapeutics

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Genetic, metabolic, and lifestyle modifications can cause elevations of lipoproteins that contribute to atherosclerotic lesions over time. In the modern world with life extension from many improvements in medicine and public health, most humans live long enough to develop atherosclerosis with concentrations of blood plasma lipoproteins that are very common. Familial abnormalities are prevalent and provide additional challenges in identifying unhealthy but treatable values of low-density (LDL) and very low-density lipoproteins (VLDL). Multiple community studies and clinical trials have provided guidance on selecting targets and new tools that make possible effective goals of treatment. Lipid-lowering drugs are making it possible to achieve those goals and place responsibility on physicians to master the art of preventing atherosclerotic events. Lipoprotein management remains a very focused effort and requires an artful individualized approach for each patient. Few skills are more important for healthcare providers in primary care and cardiovascular medicine.

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Is it time for a paradigm shift? Inclusion of APOE on genetic dyslipidemia panels

Ison,

Mowaswes,

Durst

et al. 2024

Journal of Genetic Counseling

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APOE codes for apolipoprotein E (ApoE), which plays an important role in lipid and lipoprotein metabolism and homeostasis of tissue lipid content. Several variants in APOE have been associated with inherited dyslipidemias, and a subsequent increased risk of developing premature coronary artery disease (CAD). However, these variants and their impact on risk can be thought of on a spectrum, with some being more monogenic in nature, and others contributing in a polygenic/multifactorial manner. Despite these known associations, there is often hesitancy around ordering APOE genetic testing due to the association with Alzheimer's disease. This paper aims to catalyze discussion around APOE testing and counseling strategies, highlight the nuances around this topic, and advocate for inclusion of APOE testing on dyslipidemia panels when an inherited dyslipidemia is suspected.

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Familial dysbetalipoproteinemia: an underdiagnosed lipid disorder

Abstract: Familial dysbetalipoproteinemia is a relatively common, though often not diagnosed, lipid disorder characterized by mixed hyperlipidemia, remnant accumulation and premature cardiovascular disease, which should be treated with dietary therapy and statin and fibrate combination.

Cited by 67 publications

References 51 publications

Severe Combined Dyslipidemia With a Complex Genetic Basis

Severe Combined Dyslipidemia With a Complex Genetic Basis

Clinical Lipidology and the Prevention of Vascular Disease: Time for Personalized Therapy

Is it time for a paradigm shift? Inclusion of APOE on genetic dyslipidemia panels

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