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Atherosclerosis
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
LDL originates from the degradation of VLDL. This process is reversible and dependent on the degree of triglyceride hydrolysis by lipoprotein lipase and on the rate of removal of cholesterol and phospholipids. A decreased rate of LDL production and lower plasma cholesterol levels have been found in patients with hypobetalipoproteinemia, a rare autosomal dominant disorder.336 LDL may exert cytotoxic actions.651
Atherosclerosis and Coronary Heart Disease
Published in Victor A. Bernstam, Pocket Guide to GENE LEVEL DIAGNOSTICS in Clinical Practice, 2019
The absence of apo B precludes the formation of chylomicrons and very low-density lipoprotein (VLDL) and LDL particles. Genetic linkage studies identified defects in the apo B gene in homozygous hypobetalipoproteinemia. In the other condition, abetalipoproteinemia, no defect of the apo B gene has been found and the genetic basis of the disease is not understood, and a posttranslational defect or a mutation in other gene(s) encoding factors involved in lipoprotein assembly or secretion appear to be at fault. A form of familial hypobetalipoproteinemia has also been described, in which a dominantly transmitted mutation in a gene other than the apo B gene is responsible for the low plasma cholesterol and apo B-carrying lipoproteins.
Peripheral neuropathies
Published in Peter R Wilson, Paul J Watson, Jennifer A Haythornthwaite, Troels S Jensen, Clinical Pain Management, 2008
Ravikiran Shenoy, Katherine Roberts, Praveen Anand
Tangier disease, a disorder of lipoprotein transport, can be associated with neuropathy with marked loss of pain sensation. Neuropathy can be transient, can be relapsing and asymmetrical, or can be slowly progressing and symmetrical with onset in upper or lower limbs. It may simulate syringomyelia, especially when the onset is in the upper limbs. Studies have shown than Tangier disease is associated with lancinating pains.62 Other features that may be associated are corneal opacities, enlarged tonsils, and hepatosplenomegaly. Biochemical abnormalities include hypocholesterolemia and normal or elevated triacylglycerol levels. Normal or elevated triacylglycerol levels help in distinguishing this condition from abetalipoproteinemia and hypobetalipoproteinemia. Nerve biopsy reveals loss of small myelinated and unmyelinated fibers.
Novel emerging therapies in atherosclerosis targeting lipid metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Manasvi Gupta, Colin Blumenthal, Subhankar Chatterjee, Dhrubajyoti Bandyopadhyay, Vardhmaan Jain, Carl J Lavie, Salim S. Virani, Kausik K Ray, Wilbert S Aronow, Raktim K Ghosh
As described above, angiopoietin-like 3 protein (ANGPTL3) inhibits LPL to reduce uptake of TGs from particles like VLDL thus increasing TG and LDL-C levels. In a new form of primary hypobetalipoproteinemia, mutations in the ANGPTL3 gene have been recognized as a cause in 10% of cases, even with a normal apoB gene [58]. Evinacumab, a human monoclonal antibody, is an inhibitor of ANGPTL3 designed to reduce TGs, non-HDL-C, and LDL-C by increasing activity of LPL and other associated enzymes. Phase I studies investigating both intravenous and subcutaneous administration demonstrated maximum reductions of TGs by 88.2% and LDL-C by 22.8%, though HDL also fell by a maximum of 37.7% [59]. A phase II study was equally promising with reductions of LDL-C by 49 ± 23%, TGs by 47%, and apolipoprotein B by 46 ± 18% at 4 weeks in 9 patients with HoFH [60]. Individuals with ANGPTL3 mutations have also been shown to have lower odds of CAD with an odds ratio of 0.61 (P < 0.001) [60]. Future studies aim to further characterize efficacy and safety in patients with persistent hypercholesterolemia, FH, and those at high risk for acute pancreatitis due to severe hypertriglyceridemia.
Preclinical discovery and development of evolocumab for the treatment of hypercholesterolemia
Published in Expert Opinion on Drug Discovery, 2020
Etienne Khoury, Diane Brisson, Daniel Gaudet
Importantly, the cardiovascular health condition in individuals naturally carrying these identified PCSK9 loss-of-function mutations was excellent. A study by Cariou B. et al. described a case of two women and a man without significant health issues showing hypobetalipoproteinemia and diminished levels of LDL-C as low as 0.4 mmol/L (15.5 mg/dL) with a complete lack of PCSK9 expression [45]. Another case of a compound heterozygous 32-year-old African American with no circulating PCSK9 was also shown to have LDL-C levels reaching 0.36 mmol/L (14 mg/dL) and reported no significant impact on his overall health status [46]. Such LDL-C levels are also encountered in other cases, as, for example, the ones with naturally occurring loss-of-function carriers in Apo B (i.e. hypobetalipoproteinemia) or microsomal triglyceride transfer protein (MTTP) (i.e. abetalipoproteinemia). The association between PCSK9 loss-of-function mutations, low levels of LDL-C and reduced incidence of CVD became well established and PCSK9 inhibition was then considered to be the next breakthrough target for CVD risk management [47].
Lessons from chylomicron retention disease: a potential new approach for the treatment of hypercholesterolemia?
Published in Expert Opinion on Orphan Drugs, 2018
Diagnosing this extremely rare disease (probably fewer than 1 in 1,000,000 people worldwide have this autosomal recessive disease) will be the first challenge for the physician. Until now, around 60 cases have been described; but only 40 with their genotype, including about 20 different mutations. Furthermore, the nonspecificity of the initial symptoms (diarrhea and steatorrhea, abdominal distension, vomiting and a rapid failure to thrive) explain the delayed diagnosis. Only one-third of children described in the literature were diagnosed with CMRD during their first year of life [10]. Therefore, a newborn with a chronic diarrhea without any confirmed classical diagnosis should have a lipid profile performed. A severe decrease in total and low-density lipoprotein (LDL) cholesterol (50% normal value) but a moderate decrease in high-density lipoprotein (HDL) and normal triglycerides (TG). This is very different in patients with other intestinal primary hypocholesterolemias associated with intestinal malabsorption, namely abetalipoproteinemia (ABL) and homozygous familial hypobetalipoproteinemia type I (FHBL-1), who have almost undetectable LDL, a normal HDL, and very low TG levels.