Acute hypertriglyceridaemic pancreatitis in a pregnant Indian: a new lipoprotein lipase gene mutation

Murugasu, C G; Armstrong, G. R.; Creedon, G.; Cavanna, J.; Galton, D. J.; Tomkin, G.H.

doi:10.1177/014107689809100410

Cited by 12 publications

(13 citation statements)

References 4 publications

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“…They also tested the function of the new mutations and the effect of three previously discovered mutations: Q148X, Q139X and G185C. Gestational HTG has been reported in patients carrying different -variants of LPL [48,49], and it is suggested to be a result of increased VLDL secretion during pregnancy to overwhelm the enzymatic capability of the mutated LPL [49]. She was also heterozygous for the common, S19W polymorphism and homozygous for LPL W86G of which a variation was previously reported in a pediatric type Type I hyperlipoproteinemia [47].…”

Section: The First Point Mutationsmentioning

confidence: 99%

Mutations of the Apolipoprotein A5 Gene with Inherited Hypertriglyceridaemia: Review of the Current Literature

Duga¹,

Sümegi²,

Kisfali³

et al. 2012

Current Medicinal Chemistry

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Apoliporotein A5 (APOA5), a member of the apolipoprotein family, plays a key regulatory role in triglyceride (TG) metabolism. Even though the exact biochemical background of its mechanism is not yet fully understood, diseases associated with this particular gene highlighted its key role in the metabolism of triglycerides in humans. Naturally occurring functional variants of the gene and their natural major haplotypes are known to associate with moderately elevated triglyceride levels, and are also known to confer risk or protection for major polygenic diseases, like coronary heart disease, stroke, or metabolic syndrome. On the other hand, case reports and even robust resequencing studies verified APOA5 mutations as underlying genetic defects behind extreme hypertriglyceridemic phenotype. Soon after the recognition of the first cases, there were indications which suggest the existence of less frequent genetic variants which, in combination with the common allelic variants of the gene, can define haplotypes that are associated with substantial triglyceride level increase. In addition, it became evident, that there are rare mutations of the APOA5 gene which can be associated with specific complex phenotypes and different types of hyperlipoproteinemia, which includes extremely high triglyceride levels with multiple organ pathology. These rare mutations may cause inheritable hypertriglyceridemia, but they presented at a low frequency and could not be captured by standard genotyping array screenings. The identification of new mutations still relies on the direct sequencing of APOA5 gene of patients with hypertriglyceridemia with an unusual pattern, individually or in huge resequencing studies.

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Section: The First Point Mutationsmentioning

confidence: 99%

Mutations of the Apolipoprotein A5 Gene with Inherited Hypertriglyceridaemia: Review of the Current Literature

Duga¹,

Sümegi²,

Kisfali³

et al. 2012

Current Medicinal Chemistry

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“…Homozygous LPL deficiency occurs in approximately 1/10 6 in the general British population. Further, mild hypertriglyceridemia in patients with heterozygous LPL deficiency may pass unnoticed until some environmental stress is placed upon the already defective lipolytic system, such as pregnancy or use of estrogen‐containing contraceptives and may lead to severe hypertriglyceridemia 3,4 . The prevalence of the heterozygous LPL deficiency is estimated to be 1:500 4 .…”

Section: Discussionmentioning

confidence: 99%

Severe, gestational, non‐familial, non‐genetic hypertriglyceridemia

Eskandar¹,

Eckford²,

Roberts

2007

J of Obstet and Gynaecol

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Severe hypertriglyceridemia is a rare condition in pregnancy. All the cases of severe gestational hypertriglyceridemia that have been reported previously in the literature were caused by genetic mutations or familial hypertriglyceridemia secondary to lipoprotein lipase deficiency or apolipoprotein C-II deficiency. We report the first case of severe, non-genetic, non-familial, pregnancy-induced hypertriglyceridemia. The genetic underlying causes were excluded by molecular genetic investigation. The reported case was managed solely by strict dietary control. Hypertriglyceridemia was diagnosed incidentally during pregnancy, in this case, while taking a blood sample to check her hemoglobin level. Acute pancreatitis, which is a relatively common life threatening complication of this condition, was avoided. This report reviews the subtypes of hyperlipidemia, clinical picture, antenatal management and its effect on pregnancy and vice versa. It is important that the clinician has a clear understanding of the normal lipid profile during pregnancy, the clinical picture, the potential complications, available treatment options of hypertriglyceridemia particularly during pregnancy. The timing and route of delivery should be individualized.

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“…15 Interestingly, the E255G proband only expressed severe HyperTG during her 2 pregnancies. Gestational HyperTG has been reported in patients homozygous or compound heterozygotes for LPL variants 21,22 and is suggested to be related to increased VLDL secretion from the liver, especially in the third trimester of pregnancy, overwhelming the hydrolytic capability of the mutant LPL. 22 ApoAV-G255 does show some reduced functionality and is less effective in activating LPL (as seen when VLDL or lipid emulsion were the TG-source), and this could exacerbate the HyperTG.…”

Section: Dormeister Et Al Novel Apoav Variants and Their Effects In Vmentioning

confidence: 99%

“…21,22 and is suggested to be related to increased VLDL secretion from the liver, especially in the third trimester of pregnancy, overwhelming the hydrolytic capability of the mutant LPL. 22 ApoAV-G255 does show some reduced functionality and is less effective in activating LPL (as seen when VLDL or lipid emulsion were the TG-source), and this could exacerbate the HyperTG. However this variant occurred at a carrier frequency of 1.7% in a study of T2D Indian Asians and was not associated with TG levels that differed significantly from noncarriers.…”

mentioning

confidence: 99%

Effects of Six APOA5 Variants, Identified in Patients With Severe Hypertriglyceridemia, on In Vitro Lipoprotein Lipase Activity and Receptor Binding

Dorfmeister

Zeng

Dichlberger

et al. 2008

ATVB

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Objective-The purpose of this study was to identify rare APOA5 variants in 130 severe hypertriglyceridemic patients by sequencing, and to test their functionality, since no patient recall was possible. Methods and Results-We studied the impact in vitro on LPL activity and receptor binding of 3 novel heterozygous variants, apoAV-E255G, -G271C, and -H321L, together with the previously reported -G185C, -Q139X, -Q148X, and a novel construct -⌬139 to 147. Using VLDL as a TG-source, compared to wild type, apoAV-G255, -L321 and -C185 showed reduced LPL activation (Ϫ25% [Pϭ0.005], Ϫ36% [PϽ0.0001], and Ϫ23% [Pϭ0.02]), respectively). ApoAV-C271, -X139, -X148, and ⌬139 to 147 had little affect on LPL activity, but apoAV-X139, -X148, and -C271 showed no binding to LDL-family receptors, LR8 or LRP1. Although the G271C proband carried no LPL and APOC2 mutations, the H321L carrier was heterozygous for LPL P207L. The E255G carrier was homozygous for LPL W86G, yet only experienced severe hypertriglyceridemia when pregnant. Key Words: apolipoprotein AV Ⅲ LDL-R family Ⅲ LR8 Ⅲ LRP1 Ⅲ HSPG-bound LPL P remature truncations of APOA5, Q139X, Q148X, and the IVS3ϩ3gϾc are associated with severe hypertriglyceridemia (HyperTG), 1-3 behaving as phenocopies of lipoprotein lipase (LPL) deficiency. These rare APOA5 variants do not always lead to a deficiency in circulating plasma apoAV, and carriers present with a range of apoAV levels (reviewed in 4 ). Kao et al 5 identified a common polymorphism G185C in a Taiwanese study which occurs at a minor allele frequency of 0.04 in controls but at a 6.3-fold higher frequency of 0.27 in hypertriglyceridemic patients (PϽ0.001). Conclusion-TheApoAV is present on chylomicrons, VLDL, and HDL, but not on IDL or LDL, suggesting that VLDL-containing apoAV is cleared before the lipolytic cascade. 6 One function of apoAV is to activate LPL, and Apoa5 knockout mice have 4-fold higher TG levels than wild type. [7][8][9] Whereas LPL transgenic mice can rescue Apoa5 knockout mice from HyperTG, this is not entirely reciprocal 8 suggesting that the effect of apoAV on plasma TG is dependent on heparinsulfate proteoglycan (HSPGs)-bound LPL. 7,8 In addition, apoAV-dependent TG catabolism acts by enhancing receptormediated endocytosis via members of the LDL-receptor (LDLR) family. 10,11 We have identified 3 novel APOA5 missense variants (E255G, G271C, H321L) in patients with TG levels Ͼ10 mmol/L. Although LPL and APOC2 variants had been excluded for the G271C carrier, the coding exons of LPL and APOC2 were sequenced in the 2 other probands. Because family studies were not possible, the APOA5 variants were expressed in vitro together with G185C, Q139X, Q148X. 1,2,5 In addition we designed a deletion construct ⌬139 to 147, to MethodsSee supplemental methods (available online at http://atvb.ahajournals. org) for full details. PatientsIn total 130 patients with TG levels Ͼ10 mmol/L were recruited into the study; seven patients from the UK, 28 patients from the Netherlands with LPL and APOC2 mutations excluded, and 95 p...

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Acute hypertriglyceridaemic pancreatitis in a pregnant Indian: a new lipoprotein lipase gene mutation

Cited by 12 publications

References 4 publications

Mutations of the Apolipoprotein A5 Gene with Inherited Hypertriglyceridaemia: Review of the Current Literature

Mutations of the Apolipoprotein A5 Gene with Inherited Hypertriglyceridaemia: Review of the Current Literature

Severe, gestational, non‐familial, non‐genetic hypertriglyceridemia

Effects of Six APOA5 Variants, Identified in Patients With Severe Hypertriglyceridemia, on In Vitro Lipoprotein Lipase Activity and Receptor Binding

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