1/12. Triglyceride-induced diabetes associated with familial lipoprotein lipase deficiency.Raised plasma triglycerides (TGs) and nonesterified fatty acid (NEFA) concentrations are thought to play a role in the pathogenesis of insulin-resistant diabetes. We report on two sisters with extreme hypertriglyceridemia and overt diabetes, in whom surgical normalization of TGs cured the diabetes. In all of the family members (parents, two affected sisters, ages 18 and 15 years, and an 11-year-old unaffected sister), we measured oral glucose tolerance, insulin sensitivity (by the euglycemic-hyperinsulinemic clamp technique), substrate oxidation (indirect calorimetry), endogenous glucose production (by the [6,6-2H2]glucose technique), and postheparin plasma lipoprotein lipase (LPL) activity. In addition, GC-clamped polymerase chain reaction-amplified dna from the promoter region and the 10 coding LPL gene exons were screened for nucleotide substitution. Two silent mutations were found in the father's exon 4 (Glu118 Glu) and in the mother's exon 8 (Thr361 Thr), while a nonsense mutation (Ser447 Ter) was detected in the mother's exon 9. Mutations in exons 4 and 8 were inherited by the two affected girls. At 1-2 years after the appearance of hyperchylomicronemia, both sisters developed hyperglycemia with severe insulin resistance. Because medical therapy (including high-dose insulin) failed to reduce plasma TGs or control glycemia, lipid malabsorption was surgically induced by a modified biliopancreatic diversion. Within 3 weeks of surgery, plasma TGs and NEFA and cholesterol levels were drastically lowered. Concurrently, fasting plasma glucose levels fell from 17 to 5 mmol/l (with no therapy), while insulin-stimulated glucose uptake, oxidation, and storage were all markedly improved. Throughout the observation period, plasma TG levels were closely correlated with both plasma glucose and insulin concentrations, as measured during the oral glucose tolerance test. These cases provide evidence that insulin-resistant diabetes can be caused by extremely high levels of TGs.- - - - - - - - - - ranking = 1keywords = hypertriglyceridemia (Clic here for more details about this article) |
2/12. A family-based study of hyperinsulinemia and hypertriglyceridemia in heterozygous lipoprotein lipase deficiency.CASE REPORT: A case is presented of predisposing a patient's father with obligate heterozygous lipoprotein lipase (LPL) deficiency to mild hypertriglyceridemia in Japanese I-family members (n=8) with patient DI, who was a compound heterozygote for a novel missense mutation of G154V (GG(716)C-->GTC/Gly(154) Val) in exon 5 and a novel splice mutation (Int8/5'-dss/t( 2)c; a T-to-C transition in the invariant GT at position 2 of the 5' donor splice site (dss)) in intron 8 of the LPL gene. RESULTS: The patient's father and paternal grandmother were heterozygotes for the Int8/5'-dss/t( 2)c allele, while the patient's mother and maternal grandmother were heterozygotes for the G154V allele. These four heterozygous carriers with one defective LPL allele showed 45-57% of the mean LPL activity and mass in the post-heparin plasma (PHP) observed in normal individuals. Among the four heterozygous carriers, the patient's father, who was <40 years old, nonobese and hyperinsulinemia, manifested mild hypertriglyceridemia (type IV hyperlipoproteinemia). The remaining three healthy heterozygous carriers (two were >40 years old and the other was <40 years old) were all normolipidemic state. CONCLUSION: In this family, hyperinsulinemia as a marker of insulin resistance may be a strong determinant of hypertriglyceridemia in the carrier with heterozygous LPL deficiency.- - - - - - - - - - ranking = 7keywords = hypertriglyceridemia (Clic here for more details about this article) |
3/12. Successful pregnancy outcome in a patient with severe chylomicronemia due to compound heterozygosity for mutant lipoprotein lipase.OBJECTIVES: Familial chylomicronemia syndrome is characterized by massive accumulation of plasma chylomicrons, which typically results from an absolute deficiency of lipoprotein lipase (LPL). Chylomicronemia in pregnancy is a rare, but serious clinical problem and can be found in patients with underlying molecular defects in the LPL gene. We report the course and treatment of an 18 yr-old primigravida who had LPL deficiency and hypertriglyceridemia since birth. We also analyzed the molecular basis of her LPL deficiency. DESIGN AND methods: The patient's antenatal course was complicated by extreme elevations of plasma triglycerides. Her management included a very low fat diet, pharmacotherapy with gemfibrozil in the third trimester, and intermittent hospitalization with periods of fasting supplemented by IV glucose feeding. We used dna sequencing to determine whether mutations in LPL were present. RESULTS: At 38 weeks of gestation, labor was induced, and the patient delivered a healthy 2.77 kilogram male. Postnatal triglycerides fell to prenatal levels. dna sequencing showed that she was a compound heterozygote for mutant LPL: I > T194 and R > H243. CONCLUSIONS: This experience indicates that vigilance is required during pregnancy in patients with familial chylomicronemia due to mutant LPL. gemfibrozil was used in this patient without apparent adverse effects. Compound heterozygosity for LPL mutations is an important underlying mechanism for LPL deficiency.- - - - - - - - - - ranking = 1keywords = hypertriglyceridemia (Clic here for more details about this article) |
4/12. Chylomicronemia caused by lipoprotein lipase gene mutation related to a hyper-response of insulin secretion to glucose.A 39-year-old man with lipoprotein lipase (LPL) deficiency (height 177.7 cm, body weight 67 kg, and body mass index 21.2 kg/m2) showed severe hypertriglyceridemia (2,032 mg/dl). LPL activity and concentration were markedly low in postheparin plasma. LPL gene analysis revealed a homozygous mutation, Asp204 --> Glu in exon 5. fasting plasma glucose (81 mg/dl) and insulin (2.7 microU/ml) levels were normal. plasma glucose pattern during oral glucose (75 g) tolerance test was normal, however 30 minutes after glucose-loading the insulin secretion unexpectedly increased to 89.4 microU/ml. These data suggested that chylomicronemia might be related to a hyper-response of insulin secretion to glucose without obesity.- - - - - - - - - - ranking = 1keywords = hypertriglyceridemia (Clic here for more details about this article) |
5/12. Type I hyperlipoproteinemia caused by lipoprotein lipase defect in lipid-interface recognition was relieved by administration of medium-chain triglyceride.We have previously reported lipoprotein lipase with a defect of lipid-interface recognition in a patient with type I hyperlipoproteinemia. In this patient, lipoprotein lipase from post-heparin plasma (PHP) hydrolyzed monomeric substrate tributyrin, but scarcely hydrolyzed triolein emulsified with Triton X-100 and that in very-low-density lipoproteins ([VLDL] d < 1.006 g/mL), and did not bind to VLDL. The triglyceride (TG) level of this patient did not decrease to less than 1,000 mg/dL with a low-fat diet (1,400 kcal containing 10 g fat/d). When the patient took 30 g medium-chain TG (MCT) in addition to the 1,400-kcal diet, her serum TG level decreased to 250 mg/dL and her clinical signs improved. The low clearance rate of serum TG with heparin injection improved after intake of MCT. Caproic acid levels were maintained at 1.4% and 2.6% in chylomicrons and VLDL after MCT intake, respectively. The patient's lipoprotein lipase hydrolyzed triolein emulsified with 2% tricaprin at the same rate as that of control lipoprotein lipase. The patient's lipoprotein lipase-catalyzed hydrolyzing rate of triolein in chylomicrons obtained after MCT administration was also enhanced up to 70% of that of control lipoprotein lipase. These findings suggest that hypertriglyceridemia caused by lipoprotein lipase with a defect in lipid-interface recognition could be relieved with the administration of medium-chain TG, and that one of the mechanisms of this effect might be a modification of TG-rich lipoproteins by MCT.- - - - - - - - - - ranking = 1keywords = hypertriglyceridemia (Clic here for more details about this article) |
6/12. ApoC-IIParis2: a premature termination mutation in the signal peptide of apoC-II resulting in the familial chylomicronemia syndrome.The chemical mismatch method has been utilized to screen for mutations in the apoC-II gene of a patient with familial chylomicronemia and apoC-II deficiency. Cleavage of heteroduplexes formed between normal and patient dna strands with hydroxylamine and osmium tetroxide readily localized a mutation near base 2660 of the mutant apoC-II. sequence analysis of PCR amplified patient dna in the mismatched region localized by this method identified the substitution of a thymidine (T) for a cytosine (C) at base 2668 in exon 2 of the patient's gene within a CpG dinucleotide. The C to T transition in the apoC-IIParis2 gene leads to the introduction of a premature termination codon (TGA) at a position corresponding to amino acid-19 of the signal peptide of apoC-II and the formation of a new Nla III restriction enzyme site absent in the normal apoC-II gene. Consistent with the history of consanguinity in this kindred, amplification of dna isolated from the proband's parents by the polymerase chain reaction and digestion with Nla III established that the proband is a true homozygote for this genetic defect. Analysis of the patient's plasma by two-dimensional gel electrophoresis and immunoblotting failed to detect any plasma apoC-II. Thus, we have identified a novel mutation in the apoC-II gene of a patient with apoC-II deficiency from a paris kindred presenting with severe hypertriglyceridemia and chylomicronemia.(ABSTRACT TRUNCATED AT 250 WORDS)- - - - - - - - - - ranking = 1keywords = hypertriglyceridemia (Clic here for more details about this article) |
7/12. A novel substitution at the translation initiator codon (ATG-->ATC) of the lipoprotein lipase gene is mainly responsible for lipoprotein lipase deficiency in a patient with severe hypertriglyceridemia and recurrent pancreatitis.A patient with severe hypertriglyceridemia and recurrent pancreatitis was found to have significantly decreased lipoprotein lipase (LPL) activity and normal apolipoprotein c-ii concentration in post-heparin plasma. dna analysis of the LPL gene revealed two mutations, one of which was a novel homozygous G-->C substitution, resulting in the conversion of a translation initiation codon methionine to isoleucine (LPL-1). The second was the previously reported heterozygous substitution of glutamic acid at residue 242 with lysine (LPL-242). in vitro expression of both mutations separately or in combination demonstrated that LPL-1 had approximately 3% protein mass and 2% activity, whereas LPL-242 had undetectable activity but normal mass. The combined mutation LPL-1-242 exhibited similar changes as for LPL-1, with markedly reduced mass, and for LPL-242, with undetectable activity. These results suggest that the homozygous initiator codon mutation rather than the heterozygous LPL-242 alteration was mainly responsible for the patient phenotypes.- - - - - - - - - - ranking = 5keywords = hypertriglyceridemia (Clic here for more details about this article) |
8/12. A case of association between type I hyperlipoproteinemia and systemic lupus erythematosus (SLE). Effects of steroid treatment.The case of a girl aged 19 yr with hypertriglyceridemia and systemic lupus erythematosus (SLE) is described. The girl had been admitted to a Lipid Outpatient Clinic in 1981 and diagnosed as having a Type I hyperlipidemia pattern. In November 1984 the patient acutely developed a SLE syndrome. Steroid treatment led to a dramatic fall of serum triglycerides from a starting value of 2100 mg/dl to 95 mg/dl. The role of steroids in completely correcting genetically deficient lipoprotein lipase Activity (LLA) is discussed.- - - - - - - - - - ranking = 1keywords = hypertriglyceridemia (Clic here for more details about this article) |
9/12. Homozygous deletion of exon 9 causes lipoprotein lipase deficiency: possible intron-Alu recombination.We studied a homozygous deletion in the lipoprotein lipase gene at the molecular level. Comprising the end of intron 8, the whole of exon 9, and about two-thirds of intron 9, this 2.136-kb deletion caused complete lipoprotein lipase deficiency and severe hypertriglyceridemia (type I hyperlipoproteinemia). Intron 9 of a normal control subject was also sequenced in order to define the exact borders of the deletion. Up to now, only the first 0.721 kb of intron 9 had been sequenced. Thus the complete sequence of intron 9 (3.090 kb) is now available. Three Alu sequences were characterized in the normal intron 9, while the proband had only the third complete Alu sequence. The first Alu sequence was located in the deleted region, and only the left arm of the second was present, as the deletion began near its center. A stem-loop structure involving a 14-nt region towards the end of intron 8 and an Alu sequence in intron 9 might have led to the deletion. sequence analysis showed that the three Alu sequences belonged to the 40-million-year-old Alu-Sa subclass.- - - - - - - - - - ranking = 1keywords = hypertriglyceridemia (Clic here for more details about this article) |
10/12. Homozygosity for two point mutations in the lipoprotein lipase (LPL) gene in a patient with familial LPL deficiency: LPL(Asp9-->Asn, Tyr262-->His).Familial lipoprotein lipase (LPL) deficiency is an inherited disorder of lipoprotein metabolism characterized by hypertriglyceridemia and recurrent episodes of abdominal pain and pancreatitis. We have studied the genetic basis of LPL deficiency in a 62-year-old black male with undetectable pre- and post-heparin plasma LPL mass and activity, dna sequence analysis of the patient's LPL cDNA and gene as well as digestion with Bcl I and Asu I revealed that the proband is a homozygote for two separate gene defects. One mutation changed a G to an A, resulting in the conversion of amino acid 9 of the mature protein, aspartic acid (GAC), to asparagine (AAC). The second substitution, a C for a T, replaced tyrosine (TAC) at residue 262 with histidine (CAC). Northern blot analysis of monocyte-derived macrophage rna demonstrated the presence of LPL mRNA of approximately normal size and quantity when compared to control. Expression of both mutations separately (pCMV-9 and pCMV-262) or in combination (pCMV-9 262) in human embryonal kidney-293 cells demonstrated that LPL-9 had approximately 80% the specific activity of wild type LPL, but LPL-262 and LPL-9 262 had no enzymic activity, thus establishing the functional significance of the LPL-262 defect. Despite an absolute deficiency of LPL mass and activity demonstrated by analysis of patient post-heparin plasma, in vitro expression of both LPL mutants was normal, suggesting that the absence of LPL in patient post-heparin plasma was a result of altered in vivo processing. Analysis of the heparin binding properties of the mutant enzymes by heparin-sepharose affinity chromatography indicated that most of the LPL-262 mass was present in an inactive peak, which like the normal LPL monomer, eluted at 0.8 M NaCl. Thus, the Tyr262 --> His mutation may alter the stability of the LPL dimer, leading to the formation of inactive LPL-262 monomer which exhibits reduced heparin affinity. Based on these results, we propose that, in vivo, enhanced formation of LPL-9 262 monomer leads to abnormal binding of the mutant lipase to endothelial glycosaminoglycans ultimately resulting in enhanced catabolism of the mutant enzyme and lower enzyme mass in post-heparin plasma.- - - - - - - - - - ranking = 1keywords = hypertriglyceridemia (Clic here for more details about this article) |
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