Compound heterozygosity for frameshift mutations in the gene for lipoprotein lipase in a patient with early-onset chylomicronemia.
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Adolescent↗
Biomedical subjects
J L De Gennes
Publications and source records attributed to J L De Gennes.
A single Ser259Arg mutation in the gene for lipoprotein lipase causes chylomicronemia in Moroccans of Berber ancestry.
Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglyceride-rich lipoproteins. Numerous LPL gene mutations have been described as a cause of familial chylomicronemia in various populations. In general, allelic heterogeneity is observed in LPL deficiency in different populations. However, a founder effect has been reported in certain populations, such as French Canadians. Although familial chylomicronemia is observed in Morocco, the molecular basis for the disease remains unknown. Here, we report two unrelated Moroccan families of Berber ancestry, ascertained independently in Holland and France. In both probands, familial chylomicronemia manifested in infancy and was complicated with acute pancreatitis at age 2 years. Both probands were homozygous for a Ser259Arg mutation, which results in the absence of LPL catalytic activity both in vivo and in vitro. In heterozygous relatives, a partial decrease in plasma LPL activity was observed, sometimes associated with combined hyperlipidemia. This mutation previously unreported in other populations segregated on an identical haplotype, rarely observed in Caucasians, in both families. Therefore, LPL deficiency is a cause of familial chylomicronemia in Morocco and may result from a founder effect in patients of Berber ancestry.
Adolescent↗
Compound heterozygote for both rare apolipoprotein E1 (Gly127-->Asp, Arg158-->Cys) and E3(Cys112-->Arg, Arg251-->Gly) alleles in a multigeneration pedigree with hyperlipoproteinaemia.
1. A French multigeneration pedigree with hyperlipoproteinaemia was investigated for the transmission of the rare apolipoprotein E1(Gly127-->Asp, Arg158-->Cys) variant. The proband, a 46-year-old male carrying the rare apoE1 variant, presented a severe type III hyperlipoproteinaemia like his three brothers and his sister. 2. ApoE phenotyping and genotyping showed a discrepancy in the second allele carried by the proband's wife and two of her children, thus suggesting another apoE gene mutation. Cloning and sequencing of the entire exon 4 demonstrated a point mutation at codon 251, leading to an apoE3(Cys112-->Arg, Arg251-->Gly) allele. The proband's wife was normolipaemic and heterozygous for this rare isoform and the common apoE3 protein. The rare apoE3(Cys112-->Arg, Arg251-->Gly) allele has been transmitted to her two daughters. The first, aged 19, was normolipaemic and heterozygous for this allele and the common apoE2 allele. The second, carrying both the rare isoforms apoE1(Gly127-->Asp, Arg158-->Cys) and apoE3(Cys112-->Arg, Arg251-->Gly), presented a hypertriglyceridaemia at the age of 10. 3. The exploration of apoE status associated with plasma lipid levels and lipoprotein profiles in this three-generation pedigree made it possible to describe a compound heterozygote for two mutated alleles, one mutation being located in the N-terminal domain of the apoE protein and the other arising in the C-terminal domain.
Adult↗
Assessment of French patients with LPL deficiency for French Canadian mutations.
Mutations in the LPL gene show high levels of allelic heterogeneity between and within different populations. Complete LPL deficiency has a very high prevalence in French Canadians, where only three missense mutations account for > 97% of cases, most consistent with founder mutations introduced early in Quebec by French immigrants. In order to determine whether these mutations were present in France, 12 unrelated French families with defined LPL deficiency were investigated for the presence of the mutations found in French Canadians. Of the 24 expected alleles, six (25%) represented mutations in French Canadians (Gly188Glu four alleles, Asp250Asn and Pro207Leu one allele each). Comparison of French Canadian and French alleles identified the same haplotype in all carriers of the Gly188Glu and of the Asp250Asn, suggesting a common origin. In contrast, the Pro207Leu occurred on different haplotypes in France and Quebec, compatible with a different ancestral origin.
Alleles↗
Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene.
BACKGROUND: Patients with lipoprotein lipase deficiency usually present with chylomicronemia in childhood. The syndrome has been considered nonatherogenic primarily because of the low levels of low-density lipoprotein (LDL) cholesterol. We prospectively evaluated patients with lipoprotein lipase deficiency for atherosclerosis. METHODS: Evidence of carotid, peripheral, and coronary atherosclerosis was sought in four patients (two men and two women) with the phenotype of familial chylomicronemia by clinical examination over a period of 14 to 30 years and by Doppler ultrasonography, B-mode ultrasonography [corrected], and exercise-tolerance testing after the age of 40. Angiography was performed when indicated. Lipoprotein lipase deficiency was assessed in vivo and in vitro by functional assays and DNA-sequence analysis. RESULTS: All four patients had a profound functional deficiency of lipoprotein lipase with a reduced enzymatic mass due to missense mutations on both alleles of the lipoprotein lipase gene. In all four patients, peripheral or coronary atherosclerosis (or both) was observed before the age of 55. Despite following a low-fat diet in which fat composed 10 to 15 percent of the daily caloric intake, the patients had hypertriglyceridemia (mean [+/- SD] triglyceride level, 2621 +/- 1112 mg per deciliter [29.59 +/- 12.55 mmol per liter]), low plasma levels of high-density lipoprotein cholesterol (17 +/- 7 mg per deciliter [0.43 +/- 0.18 mmol per liter]), and very low levels of LDL cholesterol (28 +/- 16 mg per deciliter [0.72 +/- 0.41 mmol per liter]). Three patients had one risk factor for atherosclerosis, whereas in one male patient, heavy smoking and diabetes were associated with an accelerated course of the disease. CONCLUSIONS: Premature atherosclerosis can occur in patients with familiar chylomicronemia as a result of mutations in the lipoprotein lipase gene. Defective lipolysis may increase susceptibility to atherosclerosis in humans.
Aged↗
Complete paternal isodisomy for chromosome 8 unmasked by lipoprotein lipase deficiency.
Uniparental disomy (UPD)-the inheritance of two homologous chromosomes from a single parent-may be unmasked in humans by the unexpected appearance of developmental abnormalities, genetic disorders resulting from genomic imprinting, or recessive traits. Here we report a female patient with familial chylomicronemia resulting from complete lipoprotein-lipase (LPL) deficiency due to homozygosity for a frameshift mutation in exon 2 of the LPL gene. She was the normal term product of an unremarkable pregnancy and had shown normal development until her current age of 5.5 years. The father (age 33 years) and the mother (age 24 years) were unrelated and healthy, with no family history of stillbirths or malformations. The father was a heterozygous carrier of the mutation, whereas no mutation in the LPL gene was detected in the mother. Southern blotting did not reveal any LPL gene rearrangement in the proband or her parents. The proband was homozygous for 17 informative markers spanning both arms of chromosome 8 and specifically for the haplotype containing the paternally derived LPL gene. This shows that homozygosity for the defective mutation in the LPL gene resulted from a complete paternal isodisomy for chromosome 8. This is the first report of UPD for chromosome 8 unmasked by LPL deficiency and suggests that normal development can occur with two paternally derived copies of human chromosome 8.
Adult↗
Identification of a new apolipoprotein E variant (E2 Arg142-->Leu) in type III hyperlipidemia.
A new rare apolipoprotein E mutant was identified as we were investigating the apolipoprotein E genotype of patients with type III hyperlipidemia (HLP III). The unusual DNA restriction fragment length polymorphism profile and then the sequence analysis of a PCR amplified fragment of the proband's apo E gene revealed a simple base substitution (G-->T) at nucleotide 3836. This mutation leads to the replacement of arginine by leucine at position 142 of the mature protein. The proband carried the mutant allele at the heterozygous status with an epsilon 3 allele. Subsequently, analysis of the proband's father's apo E gene showed that same mutated allele associated with an epsilon 2 allele. The two subjects presented a dysbetalipoproteinemia in which this new apo E variant could be implicated.
Aged↗
Comparison of the efficacy of simvastatin and standard fibrate therapy in the treatment of primary hypercholesterolemia and combined hyperlipidemia.
Five multicenter, randomized, double-blind, placebo-controlled studies were conducted in France to compare the efficacy and safety of once-daily simvastatin treatment (10-40 mg/day) with conventional therapy with gemfibrozil 900 mg/day, ciprofibrate 100 mg/day, bezafibrate 400 mg/day, and fenofibrate 300 or 400 mg/day in a total of 800 patients with hypercholesterolemia. Simvastatin was associated with statistically significantly greater (p < or = 0.01) mean percent reductions in plasma low-density lipoprotein (LDL) cholesterol compared with each of the five fibrate regimens, even when administered at its recommended starting dose of 10 mg/day. Furthermore, approximately 90% of patients treated once daily with simvastatin experienced an at least 20% decrease in plasma LDL cholesterol compared with only 36 to 68% of patients treated with the individual fibrate agents (p < or = 0.05). The effectiveness of simvastatin in reducing LDL cholesterol did not differ as a function of the baseline plasma concentrations of total cholesterol or triglycerides. In contrast, the effectiveness of fibrate therapy in lowering plasma LDL cholesterol levels was significantly diminished (p < or = 0.05) among patients with triglyceride concentrations > 1.7 mmol/l. Plasma high-density lipoprotein (HDL) cholesterol levels were increased by approximately 10% after treatment with simvastatin or the fibrates. Although fibrate therapy was more effective overall in lowering plasma triglyceride levels, the effectiveness of simvastatin in reducing plasma triglyceride levels was generally 2- to 4-fold greater in patients with hypercholesterolemia associated with triglyceride levels > or = 2.3 mmol/l than in those with hypercholesterolemia associated with triglyceride levels < 2.3 mmol/l. The results of these studies confirm the superiority of simvastatin to standard fibrate therapy in reducing plasma levels of total and LDL cholesterol. They further indicate that once-daily treatment with simvastatin is effective in patients with isolated hypercholesterolemia or hypercholesterolemia associated with elevated triglyceride levels.
Anticholesteremic Agents↗
Recurrent missense mutations at the first and second base of codon Arg243 in human lipoprotein lipase in patients of different ancestries.
Mutations in the lipoprotein lipase (LPL) gene are the most common cause of familial chylomicronemia. Here we define the molecular basis of LPL deficiency in four patients of German, French, Dutch, and Chinese descent. We show that two of the probands of Dutch and Chinese origin have a previously described Arg243His mutation while the patients of German and French descent have a novel Arg243Cys substitution in their LPL gene. Haplotype analysis is in favour of two separate origins for the Arg243Cys substitution which together with the Arg243His mutation would implicate three recurrent mutations involving the first and second nucleotides of the codon encoding Arg243 of the LPL gene. The recurrent mutations affecting the first and second nucleotide of CGC coding for the normal Arg residue are support for the high mutability of CpG dinucleotides within the LPL gene.
Adult↗
Evidence of non-deficient low-density lipoprotein receptor patients in a pool of subjects with clinical familial hypercholesterolemia profile.
For this study, we selected 41 adult patients with the classic clinical diagnosis of heterozygous familial hypercholesterolemia (FH), which is characterized by a low-density lipoprotein (LDL) cholesterol level above the 95th percentile, xanthomas, and/or personal or familial cardiovascular history. We used an indirect immunocytofluorimetric assay to classify these 41 subjects according to LDL receptor function on lymphocytes. We found that LDL receptor activity was normal in nine patients. A large study of plasma lipid, lipoprotein, and apolipoprotein levels found no significant difference between patients with and without LDL receptor defect. Familial defective apolipoprotein (apo) B-100 (FDB) and LDL-binding defects were not found in the nine patients without LDL receptor defect. These results suggest that other defects in the regulation of lipoprotein metabolism are capable of giving rise to a clinical and biochemical disorder indistinguishable from classic FH.
Adult↗
[Biological efficacy of LDL apheresis in major hypercholesterolemia].
Severe hypercholesterolaemia include familial homozygous hypercholesterolaemia and certain heterozygous hypercholesterolaemias which become severe, due to spontaneous non-response to treatment or to iatrogenic side effects. Other causes include an associated overload in Lp(a) or uncontrolled atheromatous disease. Surgical treatment has been replaced by iterative LDL apheresis in these severe forms. Mean cholesterol and LDL cholesterol levels can be reduced by 41 to 63% and 49 to 68% respectively with LDL apheresis. In general, HDL cholesterol is protected in selective LDL apheresis. We observed similar decrease for apo B and LDL cholesterol levels. Fifty percent of the Lp(a) was removed in the 3 groups of patients studied.
Adolescent↗
Common and rare genotypes of human apolipoprotein E determined by specific restriction profiles of polymerase chain reaction-amplified DNA.
The three common isoforms of human apolipoprotein E (apo E) differ at positions 112 and 158 and are named E3, E4, and E2 according to phenotyping by isoelectric focusing (IEF). The polymerase chain reaction (PCR) method allows the detection of common and several rare allelic apo E variants not detected by IEF. We propose a genotyping procedure for apo E that characterizes a given allele on the basis of amplification of specific sequences of the gene followed by the action of restriction endonucleases. When the nucleotide change does not lead to a restriction site, PCR-directed mutagenesis creates the discriminant site, and the differentiation of the three common alleles and five rare variants is possible. We present here profiles of common alleles and of three rare alleles, Weisgraber [Cys112/Asp127/Cys158], Christchurch [Cys112/Ser136/Arg158], and a new rare variant [Cys112/Leu142/Cys158].
Alleles↗
Effect of pravastatin, a HMG CoA reductase inhibitor, on blood lipids and aortic lipidosis in cholesterol-fed White Carneau pigeons.
The effect of pravastatin, an inhibitor of HMG CoA reductase, on blood lipids and aortic lipidosis was studied in young cholesterol-fed White Carneau pigeons. The birds were fed with normal ('N group', n = 20) or atherogenic diet (grains + 0.4% cholesterol + 4% lard) alone ('C group', n = 20) and in association with pravastatin ('P group', n = 20). Plasma lipids and aortic intima lipidosis were studied after 3-5 and 8-12 months of the diet. Compared to the N group, pigeons from C group exhibited hypercholesterolemia (TC = 1000 mg/dl) and hyperlipoproteinemia of which level was independent of the duration of the diet. Total VLDL (VLDL+LDL)-cholesterol and apolipoprotein-B levels rose significantly 15, 8 and 4 times, respectively, whereas HDL were increased two times (P < 0.01) in females only. Macroscopically visible intima lipidosis areas covered 40% and 80% of aortic surface after 3-5 and 8-12 months of the diet. In P group, the increase in plasma lipid values was significantly lower than in WC from C group: -40% for total cholesterol (600 mg/dl) (P < 0.01), -71% for VLDL (P < 0.001), -53% for (VLDL+LDL)-cholesterol (P < 0.01) and -54% for apo-B (P < 0.05). HDL remained as high as in C group. Consequently TC/HDL-C ratio was improved and atherogenic risk of cholesterol was reduced by 41% (P < 0.05). Intima lipidosis areas were lowered by 35% (P < 0.01). We conclude that pravastatin treatment involves (1) a decrease in hypercholesterolemia and hyperlipoproteinemia and (2) a lowering in extensiveness and severity of macroscopically visible aortic lipidosis in cholesterol-fed White Carneau pigeon.
Animals↗
[Unusual mixed pituitary adenoma with gonadotropic, somatotropic hormones and prolactin].
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Adenoma↗
[Frequency of hypothyroidism in a population of hyperlipidemic subjects].
Hypothyroidism is a classical cause of hypercholesterolaemia. As we sometimes met patients with hyperlipidaemia whose thyroid state was unknown, we carried out a prospective study aimed at evaluating the frequency of hypothyroidism in a population of 1210 hyperlipidemic patients who were referred to our out-patient clinic at the La Pitié Hospital, Paris, for metabolic and cardiovascular assessment. The proportion of subjects with high thyroid-stimulating hormone (TSH) levels was 12, 56 percent, which is distinctly higher than the figures reported in previous studies in patients who were not selected for lipid abnormalities. Among those with high TSH levels, 16 had overt hypothyroidism with a low free T4 level. Analysis of lipid parameters showed that hypertriglycidaemia was frequent and did not confirm the hyperHDLaemia classically observed in hypothyroidic populations. We conclude that screening for hypothyroidism by measuring TSH values is of particular importance in patients with hyperlipidaemia, especially in the group of women over 50 years of age.
Adolescent↗
[Analgesic effect on headaches of octreotide, a somatostatin analogue, in a case of non-functioning pituitary adenoma].
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Adenoma↗
[Association of polyneuritis, plasma cell dyscrasia and Cushing's disease. A new case of "POEMS" syndrome?].
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Cushing Syndrome↗
Lipoprotein Lp(a) in homozygous familial hypercholesterolemia: density profile, particle heterogeneity and apolipoprotein(a) phenotype.
Homozygous familial hypercholesterolemia (FH) is a genetic disorder featuring a functional defect in cellular LDL receptors, marked elevation in circulating LDL concentrations, and premature atherosclerosis. The potential atherogenic role of apo B-containing lipoproteins other than LDL in this disease is indeterminate. We describe the quantitative and qualitative characteristics of Lp(a) as a function of apo(a) phenotype in a group of eight, unrelated homozygous FH patients. Plasma Lp(a) levels were significantly elevated (2.5-fold; mean 50 +/- 32 mg/dl) as compared to those in healthy subjects. The S2 isoform of apo(a) occurred most frequently (6 of eight patients); the rare B isoform presented in three patients. Plasma Lp(a) levels in homozygous FH did not correspond to those predicted by apo(a) phenotype. Analyses of the density distribution of Lp(a) and of Lp(a) particle size and heterogeneity as a function of density did not reveal any anomalies characteristic of homozygous FH. However, comparison of the hydrated density of Lp(a) particles as a function of apo(a) isoform content revealed a clear influence of isoform on this parameter; thus, in a B/S2 heterozygous patient, the density distribution of Lp(a) fractions containing isoform B alone, B and S2, and S2 alone, demonstrated that the apparent molecular weight of apo(a) plays a determining role in controlling the hydrated density and size of the resulting Lp(a) particle. Indeed, patients expressing the high molecular weight, S2 isoform uniformly displayed a dense form of Lp(a) (hydrated density approximately 1.055 g/ml). In subjects presenting two apo(a) isoforms, each isoform resided on distinct lipoprotein particles; in such cases, the plasma levels of the denser isoform predominated, suggesting differences in rates of formation, or rates of tissular catabolism, or in the plasma stability of the particles, or a combination of these mechanisms. Considered together, our data may be interpreted to suggest that the elevated circulating levels of Lp(a) in homozygous FH patients may reflect either an increased biosynthesis, or diminished catabolism via the cellular LDL receptor pathway, or a combination of both.
Adolescent↗