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J Frohlich

Publications and source records attributed to J Frohlich.

At least 55 records · Page 3Linked to original sources
PubMed1997

Effect of lipoprotein-X on lipid metabolism in rat kidney.

Lipoprotein-X (Lp-X) is found in the plasma of patients with familial lecithin: cholesterol acyltransferase (LCAT) deficiency syndromes. The majority of the patients with this disorder develop progressive glomerulosclerosis. In this study, the effect of Lp-X on lipid metabolism in perfused rat kidney was investigated. Lp-X was isolated from plasma of patients with familial LCAT deficiency by sequential ultracentrifugation and gel filtration column chromatography. Rat kidneys were perfused for 1-2 h with Krebs-Henseleit buffer containing 20 microM [1-(14)C]acetate or 20 microM [Me-3H]choline. In the presence of Lp-X, no significant difference in the incorporation of radioactivity into triglycerides, cholesterol, phosphocholine, CDP-choline and sphingomyelin was observed. However, incorporation of radioactivity into cholesteryl esters and phosphatidylcholine was significantly elevated in Lp-X perfused kidneys. The contents of cholesterol, cholesteryl esters and phosphatidylcholine were also significantly increased in Lp-X perfused kidneys. The increase in lipid content in the Lp-X perfused kidney is attributed to the direct deposition of Lp-X lipids into the organ. The increase in the labelling of cholesteryl esters was attributed to the increase of available substrate (cholesterol) for the acyl-CoA:cholesterol acyltransferase (ACAT) reaction. The increase in phosphatidylcholine labelling was caused by a reduced turnover of the newly synthesized labelled phosphatidylcholine during Lp-X perfusion.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1997

The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes.

Lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes represent a group of rare genetic disorders of HDL metabolism that have been the subject of a large number of clinical, biochemical, and genetic studies. Of special interest are patients with LCAT-related disorders with severe HDL deficiency and the apparent absence of premature atherosclerosis. This finding is inconsistent with the general concept that low HDL cholesterol levels are an obligate risk factor for atherosclerosis. In this review, we describe 36 natural mutations in the LCAT gene that result in either familial LCAT deficiency (FLD) or the milder phenotype known as fish-eye disease (FED). We propose a new classification of the natural mutations of the LCAT gene that are described to date. The defects are divided into four classes based on both the clinical and biochemical characterization of the patient and data that were obtained from the functional assessment of the mutant proteins. We define FLD-associated mutations that underlie a complete or nearly complete loss of LCAT activity due to null mutations (Class 1), and missense mutations (Class 2), respectively. In addition, we distinguish two classes of FED-associated mutations (Classes 3, 4) that underlie a partial impairment of LCAT activity but differ in their lipoprotein substrate specificity. In addition, we review the evidence of atherosclerosis in subjects with LCAT deficiency syndromes. The observation that 6 (all males) of a total of 19 FED subjects suffered from premature CAD (as defined by < 55 years of age and < 60 years of age for women and men, respectively) challenges the earlier assumption that the FED phenotype is not associated with increased risk of CAD. However, premature CAD remains an unusual clinical complication in FLD subjects.

Adolescent↗
PubMed1996

The pathology of cornea in Tangier disease (familial high density lipoprotein deficiency).

AIMS: To clarify the underlying causes of corneal opacification in Tangier disease. METHODS: Both corneas were removed at death from a 62 year old man with Tangier disease, and were examined by direct and transmission electron microscopy, histochemistry, biochemical analysis by thin-layer and gas-liquid chromatography after extraction, and by differential scanning calorimetry. RESULTS: Membranous inclusions in the stroma were seen on transmission electron microscopy. Direct analysis confirmed enrichment with phospholipids and cholesterol, with acyl patterns and proportions as ester broadly similar to those of normal cornea. Tangier cornea showed major thermotropic phase transitions in the range 28-37 degrees C, peak 30-33 degrees C, extending above profiles of normal clear cornea and without the complexity of those seen with cornea with heavy arcus involvement. CONCLUSIONS: Lipid accumulation underlies corneal opacification in Tangier disease. The excess material is mainly phospholipid and cholesterol esters. As at other sites which are below body core temperature, notably tonsil, accumulation may be enhanced by local impaired mobilisation of material as the phase transitions of the excess lipid present extend above ambient corneal temperatures.

Calorimetry, Differential Scanning↗
PubMed1996

Measurement of fractional esterification rate of cholesterol in plasma depleted of apoprotein B containing lipoprotein: methods and normal values.

The distribution of differently sized HDL particles in the plasma can be assessed by measurement of the fractional rate of cholesterol esterification (FERHDL). We have characterized the isotopic assay and compared it to the enzymatic measurement of the decrease in HDL free cholesterol (mass assay). The normal values of FERHDL were established in 116 apparently healthy individuals. The isotopic assay is particularly sensitive to changes in the incubation temperature above 37 degrees C. The reproducibility of the assay in aliquots of plasma stored at -20 degrees C and -70 degrees C for 3 months and even up to 2 years was high. Intraindividual variability of FERHDL is low. In the subjects in whom FERHDL was measured over a 3-month and 2-5 years' period, FERHDL showed a low variability (97.5 +/- 2.6% and 101 +/- 6.0% respectively in a paired t-test). Comparison of the isotopic assay and the mass assay revealed that the isotopic assay was much more reproducible. Normal values of FERHDL and the HDL subspecies distribution (using gradient gel electrophoresis) were established in 63 men and 56 women. The average values of FERHDL were significantly higher in men (16.8 +/- 4.5%/h) than in women (10.6 +/- 3.6%/h) and correlated well with the distribution of the HDL subspecies. FERHDL radioassay as a highly reproducible method for the assessment of HDL subspecies distribution which may be suitable for both retrospective and prospective studies of diseases of atherogenous origin.

Adult↗
PubMed1995

Hydrocephalus, mineralizing angiopathy, hypercholesterolemia, and hyperlipoprotein (a).

A boy born at 34 weeks gestation with initially normal development presented with acute hydrocephalus at 22 months. Subsequently his development has been slow and complicated clinically by epilepsy. Upon extensive investigation, he has been found to have extremely elevated lipoprotein(a) levels, hypercholesterolemia (familial), and lesions of the cortex and meninges. Radiologic studies have disclosed a mineralizing angiopathy.

Acute Disease↗
PubMed1995

Patients with apoE3 deficiency (E2/2, E3/2, and E4/2) who manifest with hyperlipidemia have increased frequency of an Asn 291-->Ser mutation in the human LPL gene.

Approximately 1% to 2% of persons in the general population are homozygous for a lipoprotein receptor-binding defective form of apoE (apoE2/2). However, only a small percentage (2% to 5%) of all apoE2/2 homozygotes develop type III hyperlipoproteinemia. Interaction with other genetic and environmental factors are required for the expression of this lipid abnormality. We sought to investigate the possible role of LPL gene mutations in the development of hyperlipoproteinemia in apoE2/2 homozygotes and in apoE2 heterozygotes. As a first step, we performed DNA sequence analysis of all 10 LPL coding exons in 2 patients with the apoE2/2 genotype who had type III hyperlipoproteinemia and identified a single missense mutation (Asn 291-->Ser) in exon 6 of the LPL gene. The mutation was then found in 5 of 18 patients with type III hyperlipoproteinemia who had the apoE2/2 genotype (allele frequency = 13.9%; P < or = 7.4 x 10(-5)) and 6 of 22 hyperlipidemic E2 heterozygous patients with the apoE3/2 and E4/2 genotype (allele frequency = 13.6%; P = 2.2 x 10(-5)). In contrast, this mutation was found in only 3 of 230 normolipidemic controls (allele frequency = 0.7%). In vitro mutagenesis studies revealed that the Asn 291-->Ser mutant LPL had approximately 60% of LPL catalytic activity and approximately 70% of specific activity compared with wild-type LPL. The heparin-binding affinity of the mutant LPL was not impaired. Our data suggest that the Asn 291-->Ser substitution is likely to be a significant predisposing factor contributing to the expression of different forms of hyperlipidemia when associated with other genetic factors such as the presence of apoE2.

Adolescent↗
PubMed1995

Severe familial HDL deficiency in French-Canadian kindreds. Clinical, biochemical, and molecular characterization.

A decreased level of HDL cholesterol (HDL-C) is the most common lipoprotein abnormality seen in people with premature coronary artery disease (CAD). In many cases, HDL-C reduction in patients with CAD may be the result of increased apo B-containing lipoprotein production by the liver with secondary hypoalphalipoproteinemia. Primary hypoalphalipoproteinemia is seen in approximately 4% of people with CAD. We report findings in four subjects with severe familial HDL deficiency (HDL-C << 5th percentile for age and sex; 0.08 to 0.38 mmol/L) in three French-Canadian kindreds with autosomal codominant inheritance. By inclusion criteria, all four subjects had normal fasting triglycerides and none were diabetic. HDL particle size by gradient gel electrophoresis revealed small HDL particles (estimated Stokes' diameter, 8.14 to 8.30 nm). Apo AI analysis by polyacrylamide gel electrophoresis and use of isoelectrofocusing gels in affected subjects revealed normal molecular weight (28.3 kD) and normal isoelectrofocusing point but a relative increase in proapoliprotein AI, with near-normal levels of proapolipoprotein AI in plasma, suggesting normal secretion of apo AI. Quantitative Southern blot analysis of the apo AI-CIII-AIV gene cluster reveals no gene rearrangements or allele deletion. Haplotypes of the apo AI gene, determined by use of the restriction enzymes Pst I, Xmn I, and Sst I and of the apo AII gene by use of the enzyme Msp I, did not reveal segregation of the low HDL-C trait with either the apo AI or the AII gene. Sequence analysis of the promoter region of the apo AI gene reveals heterozygosity for guanine-to-adenine substitution at position 76 in two kindreds with no evidence of segregation with the low HDL trait. None of the patients had mutations of the lipoprotein lipase gene common in subjects of French-Canadian descent. Haplotype analysis of the lipoprotein lipase gene did not show segregation with the low HDL trait. Plasma lecithin: cholesterol acyltransferase (LCAT) activity was found to be within normal levels in affected subjects and in nonaffected first-degree relatives. None of the affected subjects had clinical manifestations of Tangier disease. Two of the four cases examined, both men, had severe CAD and had undergone revascularization procedures. The third is a younger brother of one of these probands and the fourth is a 30-year-old woman, and both were free of clinical CAD. However, in none of the families did the low HDL trait unequivocally cosegregate with CAD.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

Role of lecithin:cholesterol acyltransferase and apolipoprotein A-I in cholesterol esterification in lipoprotein-X in vitro.

Lipoprotein-X (Lp-X) is an abnormal particle present in the plasma of patients with familial lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes or cholestatic liver disease. Compared to other lipoproteins, Lp-X contains a high content of unesterified cholesterol (30%, w/w) to phosphatidylcholine (60%, w/w). The objective of this study was to evaluate the role of LCAT and apolipoprotein A-I (apoA-I) in Lp-X metabolism in vitro and to elucidate the regulation of cholesterol esterification in this unique lipoprotein. Lp-X isolated from sera of patients with obstructive jaundice had a high content of unesterified cholesterol and phosphatidylcholine and contained apolipoprotein E, apoCs, and albumin. Although human recombinant LCAT used as an enzyme source did bind to isolated Lp-X, no cholesterol esterification was detected. However, addition of human apoA-I in the presence of albumin resulted in significant cholesterol esterification in Lp-X (Vmax 0.25 +/- 0.04 nmol/h per microgram LCAT protein). Exogenous apoA-I did not change the size of Lp-X particle as determined by quasi-elastic light scattering analysis. A reduction in Lp-X size was observed when both apoA-I and LCAT were included in the reaction mixture (from 47 nm to 42 nm). Furthermore, addition of apoA-I (but not HDL) dramatically changed the electrophoretic mobility of Lp-X from cathodic to anodic migration. Such changes are not due to displacement of apoC or apoE proteins from Lp-X by apoA-I. While increasing apoA-I concentration (up to 35 micrograms/ml) in the reaction mixture stimulated cholesterol esterification in Lp-X, addition of apoA-I at the concentration of 8 micrograms/ml inhibited cholesterol esterification in VLDL, LDL, and HDL by more than 50%. Albumin was required for the LCAT reaction to Lp-X. Our results suggest that while LCAT binds to isolated Lp-X, apoA-I is needed for the LCAT reaction to proceed. The presence of apoA-I does not result in the displacement of apoCs and apoE from Lp-X and addition of apoA-I changes the electrophoretic mobility but not the size of Lp-X.

Animals↗
PubMed1994

Evidence for impaired cellular cholesterol removal mediated by apo A-I containing lipoproteins in patients with familial lecithin: cholesterol acyltransferase deficiency.

We investigated the cholesterol reducing capacity of two species of lipoproteins containing apo A-I, one containing only apo A-I (LpA-I) and the other containing apo A-I and apo A-II (LpA-I/A-II), in 7 patients (4 homozygotes and 3 heterozygotes) with familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Interaction of normal LpA-I or LpA-I/A-II with macrophage foam cells induced a mass reduction in cholesterol from these cells and the cholesterol reducing capacity of LpA-I was greater than that of LpA-I/A-II. When foam cells were incubated with these lipoproteins from homozygotes or heterozygotes, the capacity of LpA-I and LpA-I/A-II particles to reduce cellular cholesterol was decreased by approx. 50% in the homozygotes but was increased by 25-50% in the heterozygotes. These results suggest that LpA-I and LpA-I/A-II isolated from homozygotes and from heterozygotes differ in their ability to accept cellular cholesterol. The former are poor and the latter good acceptors of intracellular cholesterol. We conclude that factors other than reverse cholesterol transport via apo A-I containing lipoproteins have to be considered to explain why homozygotes for LCAT deficiency are not at high risk for premature atherosclerosis.

Adult↗
PubMed1994

Efficacy and safety of fluvastatin in patients with non-insulin-dependent diabetes mellitus and hyperlipidemia.

The purpose of this study was to investigate the triglyceride-lowering effect of fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, in the combined hyperlipidemia of non-insulin-dependent diabetes mellitus (NIDDM). In this double-blind trial, 66 patients with NIDDM (24 men and 42 women, age 37-71), with low-density lipoprotein cholesterol (LDL-C) levels of 130-300 mg/dL (3.4-7.8 mmol/L) and triglyceride (TG) levels of 200-1,000 mg/dL (2.3-11.3 mmol/L) despite an 8-week period of diet modification, were randomized to receive either fluvastatin at 20 mg once daily (at night) or placebo for 6 weeks, followed by an increase of fluvastatin to 20 mg twice daily for an additional 6 weeks of treatment. After 12 weeks, fluvastatin decreased plasma levels of total cholesterol by 19.9% (p < 0.001), LDL-C by 24.3% (p < 0.001), TG by 15.3% (p < 0.01), very low-density lipoprotein cholesterol (VLDL-C) by 19.7% (p < 0.001), apolipoprotein (apo) B by 21.3% (p < 0.001), and apo E by 18.1% (p < 0.05), whereas high-density lipoprotein cholesterol (HDL-C) levels were increased by 4.6% (p < 0.05). Within the intermediate-density lipoprotein cholesterol (IDL-C) fraction, a constituent analysis revealed a total cholesterol reduction of 35% (p < 0.01). Greater decreases in TG were seen in patients who had higher levels of TG at baseline. Slight increases in glycemic indices and body weight were seen in both treatment groups. The occurrence of clinical and laboratory abnormalities was similar with both active treatment and placebo, and no myositis was observed. Slight increases in aspartate (ASAT; mean 5.6 U/L at the higher dose) and alanine (ALAT; mean 5.1 U/L at the higher dose) aminotransferases were not clinically significant. In this first, parallel-group placebo-controlled trial of a reductase inhibitor in a free-living NIDDM population, fluvastatin safely improved the combined TG, VLDL-C, IDL-C, LDL-C, and HDL-C abnormalities associated with NIDDM.

Adult↗
PubMed1994

Homozygous Tangier disease and cardiovascular disease.

Decreased levels of plasma high density lipoprotein (HDL) cholesterol have been associated with premature cardiovascular disease (CVD). Tangier disease is an autosomal co-dominant disorder in which homozygotes have a marked deficiency of HDL cholesterol and apolipoprotein (apo) A-I levels (both < 10 mg/dl), decreased low density lipoprotein (LDL) cholesterol levels (about 40% of normal), and mild hypertriglyceridemia. Homozygotes develop cholesterol ester deposition in tonsils (orange tonsils), liver, spleen, gastrointestinal tract, lymph nodes, bone marrow, and Schwann cells. Our purpose was to assess the prevalence of CVD in Tangier disease. We reviewed published clinical information on 51 cases of homozygous Tangier disease, report 3 new cases and provide autopsy information on 3 cases. Mean (+/- S.D.) lipid values of all cases were as follows: total cholesterol 68 +/- 30 mg/dl (32% of normal), triglycerides 201 +/- 118 mg/dl (162% of normal), HDL cholesterol 3 +/- 3 mg/dl (6% of normal) and LDL cholesterol 50 +/- 38 mg/dl (37% of normal). The most common clinical finding in these subjects (n = 54) was peripheral neuropathy which was observed in 54% of cases versus < 1% of control subjects (n = 3130). CVD was observed in 20% of Tangier patients versus 5% of controls (P < 0.05), and in those that were between 35 and 65 years of age, 44% (11 of 25) had evidence of CVD (either angina, myocardial infarction or stroke) versus 6.5% in 1533 male controls and 3.2% in 1597 female controls in this age group (P < 0.01). In 9 patients who died, 2 died prior to age 20 of probable infectious diseases, 3 of documented coronary heart disease at ages 48, 64, and 72, 2 of stroke at ages 56 and 69, one of valvular heart disease, and 1 of cancer. In three autopsy cases, significant diffuse atherosclerosis was observed in one at age 64, moderate atherosclerosis and cerebral infarction in another at age 56, but no atherosclerosis was noted in the third case who died of lymphoma at age 62. In one patient with established coronary heart disease, none of the lipid lowering agents used (niacin, gemfibrozil, estrogen or lovastatin) raised HDL cholesterol levels above 5 mg/dl. However, these agents did have significant effects on lowering triglyceride and LDL cholesterol levels. Our data indicate that there may be heterogeneity in these patients with regard to CVD risk, that peripheral neuropathy is a major problem in many patients, and that CVD is a significant clinical problem in middle aged and elderly Tangier homozygotes.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Characterization of subspecies of apolipoprotein A-I-containing lipoprotein in homozygotes for familial lecithin:cholesterol acyltransferase deficiency.

We characterized the two species of lipoproteins containing apolipoprotein A-I (apoA-I), one containing only apoA-I (LpA-I) and the other containing apoA-I and apoA-II (LpA-I/A-II), in four homozygotes for familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Two homozygotes lacked both LCAT mass and activity, whereas the other two had some residual LCAT mass and activity. In these patients, the amount of all apoA-I-containing lipoproteins was one fourth that of normal control subjects, and > 60% was LpA-I. The chemical composition of both LpA-I and LpA-I/A-II is characterized by markedly decreased ratios of neutral to polar lipids compared with those of normals and the sizes of LpA-I and LpA-I/A-II particles are shifted to smaller and larger diameter ranges when compared with those of normal particles. Changes in particle diameter are also reflected in slower electrophoretic mobilities of both LpA-I and LpA-I/A-II particles. All of these abnormalities were more evident in the two homozygotes who lacked LCAT activity. Incubation of LCAT-deficient plasma with LCAT markedly corrected the chemical and physical abnormalities in both LpA-I and LpA-I/A-II particles. These data, taken together, emphasize the importance of LCAT in modifying the chemical composition, size, and shape of LpA-I and LpA-I/A-II particles.

Adult↗
PubMed1994

Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin: cholesterol acyltransferase deficiency and fish-eye disease.

Classic (complete) lecithin:cholesterol acyltransferase (LCAT) deficiency and Fish-eye disease (partial LCAT deficiency) are genetic syndromes associated with markedly decreased plasma levels of high density lipoprotein (HDL) cholesterol but not with an increased risk of atherosclerotic cardiovascular disease. We investigated the metabolism of the HDL apolipoproteins (apo) apoA-I and apoA-II in a total of five patients with LCAT deficiency, one with classic LCAT deficiency and four with Fish-eye disease. Plasma levels of apoA-II were decreased to a proportionately greater extent (23% of normal) than apoA-I (30% of normal). In addition, plasma concentrations of HDL particles containing both apoA-I and apoA-II (LpA-I:A-II) were much lower (18% of normal) than those of particles containing only apoA-I (LpA-I) (51% of normal). The metabolic basis for the low levels of apoA-II and LpA-I:A-II was investigated in all five patients using both exogenous radiotracer and endogenous stable isotope labeling techniques. The mean plasma residence time of apoA-I was decreased at 2.08 +/- 0.27 d (controls 4.74 +/- 0.65 days); however, the residence time of apoA-II was even shorter at 1.66 +/- 0.24 d (controls 5.25 +/- 0.61 d). In addition, the catabolism of apoA-I in LpA-I:A-II was substantially faster than that of apoA-I in LpA-I. In summary, genetic syndromes of either complete or partial LCAT deficiency result in low levels of HDL through preferential hypercatabolism of apoA-II and HDL particles containing apoA-II. Because LpA-I has been proposed to be more protective than LpA-I:A-II against atherosclerosis, this selective effect on the metabolism of LpA-I:A-II may provide a potential explanation why patients with classic LCAT deficiency and Fish-eye disease are not at increased risk for premature atherosclerosis despite markedly decreased levels of HDL cholesterol and apoA-I.

Adult↗
PubMed1994

Efficacy and safety of fluvastatin in hyperlipidaemic patients with non-insulin-dependent diabetes mellitus.

In this preliminary report of a 20-week trial, 66 patients with non-insulin-dependent diabetes mellitus (NIDDM) and hyperlipidaemia who remained eligible after an 8-week dietary stabilization phase were randomly allocated to receive 20 mg of fluvastatin or placebo once daily for 6 weeks. Fluvastatin was subsequently increased to 20 mg twice daily and administered according to the same schedule, versus placebo, for a further 6 weeks. Both dosages of fluvastatin substantially improved serum lipid profiles compared with baseline and placebo. Both dosages of fluvastatin significantly reduced low-density- and very-low-density-lipoprotein (LDL, VLDL), cholesterol and triglyceride (TG) compared with placebo, and both dosages significantly elevated high-density-lipoprotein (HDL) cholesterol. The ratio of LDL to HDL was also significantly decreased. Amongst the 58 patients who completed the study, there was no evidence either of myopathy or of hepatotoxicity; mean creatine kinase values remained stable in the fluvastatin arm. Fasting glucose, glycosylated haemoglobin, and fructosamine levels were not markedly affected by active treatment. No serious adverse events attributable to the drug were reported. In conclusion, both dosages of fluvastatin appear to be effective and safe in the management of hyperlipidaemia in this outpatient, maturity-onset, diabetic population.

Adult↗
PubMed1994

High frequency of mutations in the human lipoprotein lipase gene in pregnancy-induced chylomicronemia: possible association with apolipoprotein E2 isoform.

Partial deficiency in lipolysis usually results in only mild disturbances of lipid levels. However, when this is associated with impairment of the uptake of remnant particles and increased production of triglyceride-rich lipoproteins stimulated by environmental factors such as during normal pregnancy, chylomicronemia may ensue. We have previously reported a patient who had approximately 12% of normal LPL activity and developed severe chylomicronemia during pregnancy (Ma et al. 1993. J. Clin. Invest. 91: 1953-1958). Here we report four new patients with pregnancy-induced chylomicronemia. In the nonpregnant state, these patients had mild to modest elevation of triglyceride levels ranging from 80 to 623 mg/dl (0.9-7.0 mmol/l) but during the third trimester they became severely chylomicronemic with triglyceride levels ranging from 2314 to 14,596 mg/dl (26 to 164 mmol/l). Three of these four patients had partial lipoprotein lipase (LPL) deficiency. The molecular characterization of the LPL gene in these three patients with partial LPL deficiency revealed four novel unpublished mutations. Patient #1 is a compound heterozygote for Leu252Arg and Ala261Thr mutations which are associated with 25% of normal LPL activity. In addition, she has an apoE3/2 genotype. Patient #2 is a heterozygote for a Asn291Ser substitution with 69% of LPL activity and also has an apoE3/2 genotype, while patient #3 is a heterozygote for a Trp382Stop mutation with 54% of normal LPL activity and has an apoE4/2 genotype. The fourth patient (#4) with pregnancy-induced chylomicronemia does not have LPL deficiency and has an apoE3/3 genotype. The previously reported patient (#5) who had 12% of normal LPL activity due to homozygosity for a Ser172Cys mutation also has an E3/3 genotype. Our data suggest that mutations in the LPL gene that cause partial LPL deficiency might be a frequent factor in the pathogenesis of pregnancy-induced chylomicronemia.

Adult↗
PubMed1993

Gene-environment interaction in the conversion of a mild-to-severe phenotype in a patient homozygous for a Ser172-->Cys mutation in the lipoprotein lipase gene.

Normal pregnancy is associated with a two- to threefold increase in plasma triglyceride levels, particularly in the third trimester, due both to the overproduction of VLDLs and to the possible suppression of lipoprotein lipase (LPL) activity. Numerous mutations in the human LPL gene causing complete LPL deficiency have been described, but naturally occurring mutations that result in defective LPL with partial activity have not yet been reported. Here we describe a 30-yr-old woman who was first diagnosed with LPL deficiency during pregnancy after she developed pancreatitis. Her plasma triglyceride levels remained mildly elevated at approximately 300 mg/dl (3.4 mmol/liter) after the first pregnancy but rose significantly after she became pregnant again (1800 to 2000 mg/dl) (20.2 to 22.5 mmol/liter). DNA sequence analysis of the LPL gene showed that the patient is homozygous for a Ser172-->Cys missense mutation in exon 5. In vitro mutagenesis revealed that the Ser172-->Cys mutation caused a mutant LPL protein that had residual activity higher than that seen in all eight other missense mutations in patients with LPL deficiency identified in our laboratory. We propose that some mutations in the LPL gene produce a defective LPL with partial activity, which usually leads to mild hypertriglyceridemia.

Adult↗
PubMed1993

Comparison of the short term efficacy and tolerability of lovastatin and simvastatin in the management of primary hypercholesterolemia.

OBJECTIVES: To compare the safety and efficacy of lovastatin and simvastatin in patients with primary hypercholesterolemia. METHODS: Fourteen Canadian centres participated in this double-blind, randomized, parallel-design study with a six-week screening period, a four-week placebo baseline period and an 18-week active treatment period. Patients were included in the study if their total cholesterol (TC) was at least 6.2 mmol/L and total triglycerides (TG) were 4.0 mmol/L or less at baseline. Half of the patients were in stratum I (TC 6.2 to 7.8 mmol/L at baseline and placebo period) and half in stratum II (TC greater than 7.8 mmol/L). The initial dose of lovastatin or simvastatin (20 and 10 mg/day, respectively) was doubled if the patient's cholesterol was greater than 5.2 mmol/L after six and/or 12 weeks, to a maximum of 80 mg/day lovastatin or 40 mg/day simvastatin. Of 298 randomized patients, two had baseline data only (and were excluded from the efficacy analysis), while 77 were treated with lovastatin and 74 with simvastatin in stratum I, and 72 were on lovastatin and 75 on simvastatin in stratum II. RESULTS: In stratum I, both lovastatin and simvastatin lowered TC (-26.0% in both the lovastatin and simvastatin groups), low density lipoprotein (LDL) cholesterol (-33.4% in lovastatin and -34.4% in simvastatin), TG (-11.4% in lovastatin and -16.2% in simvastatin), apolipoprotein (apo)-B (-24.8% in lovastatin and -26.3% in simvastatin) and the TC:high density lipoprotein (HDL) cholesterol ratio (from 6.65 to 4.73 in lovastatin and from 6.45 to 4.46 in simvastatin), and increased HDL cholesterol (+3.6% in lovastatin and +7.8% in simvastatin) and apo-A1 (+6.3% in lovastatin and +9.0% in simvastatin) with P < 0.001 in all within-group tests except for HDL cholesterol (P < 0.05). Similar results were obtained in stratum II for TC (-30.7% in lovastatin and -30.3% in simvastatin), LDL cholesterol (-37.6% in lovastatin and -36.8% in simvastatin), TG (-21.9% in lovastatin and -16.9% in simvastatin), apo-B (-32.0% in lovastatin and -31.7% in simvastatin), TC:HDL cholesterol ratio (from 8.62 to 5.47 in lovastatin and from 8.96 to 5.77 in simvastatin), HDL cholesterol (+9.7% in lovastatin and +7.5% in simvastatin) and apo-A1 (+7.2% in lovastatin and +8.8% in simvastatin), with P < 0.001 in all within-group tests. Serious adverse events (clinical and laboratory) were reported in four patients in the lovastatin group and three in the simvastatin group. The most reported nonserious adverse effects were gastrointestinal tract (15 patients in the lovastatin group and 16 in the simvastatin group) and musculoskeletal (14 patients in the lovastatin group and 11 in the simvastatin group). Medication was withdrawn in eight patients. CONCLUSIONS: Both lovastatin and simvastatin were found to be effective and well tolerated in each stratum. However, there were no significant differences between lovastatin and simvastatin in the treatment of moderate or severe primary hypercholesterolemia.

Anticholesteremic Agents↗